Imidazo pyrazines

ABSTRACT

Compounds of formula 
                         
and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of AML.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/453,601, filed Mar. 17, 2011, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to imidazo[1,2-a]pyrazines which act asinhibitors of Fms-like tyrosine 3 (FLT3) and are useful in theamelioration, treatment or control of cancer, specifically acute myeloidleukemia (AML).

BACKGROUND OF THE INVENTION

Kinases are known to be important cellular enzymes that regulatecellular functions such as regulating cell division and proliferation.WO 2008/047307. Fms-like tyrosine 3 (FLT3) is a receptor tyrosine kinase(RTK) that is reported to be mutated in 25-30% of acute myeloid leukemia(AML) cases. See Miguel Sanz et al., “FLT3 inhibition as a targetedtherapy for acute myeloid leukemia,” Current Opinion Oncol. (2009)21:594-600. Specifically, a mutation in the internal tandem duplication(ITD) of the fms-like tyrosine 3 (FLT3) gene is reported to be thesecond most common genetic change associated with cytogenetically normalAML. This mutation is indicated to be an important prognostic factor forthis class of patients as mutations of the ITD are associated with poordisease prognosis. Sanz Id. FLT3 is thus a recognized molecular targetfor the development of new therapies for AML. Sanz id at 596; Qi Chao etal, “Identification of . . . (AC220), a Uniquely Potent, Selective andEfficiacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor,” J. Med. Chem.(2009) 52:7808-7816. Currently, there are a number of selective FLT3inhibitors being investigated as treatments for AML (includingtandutinib and AC220), and sunitinib, a multitargeted kinase inhibitor(including FLT3), has already been approved for sale. See Chao et al.,id; Sanz et al., supra. Other inhibitors of FLT3 that are in developmentare discussed in Sanz, id, and Thomas Fischer et al., J Clinical Oncol.(2010) 28:4339-4345.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein X, R¹, R², R³ andR⁴ are as defined below.

The present invention also relates to pharmaceutical compositionscomprising one or more compounds of the invention, or a pharmaceuticallyacceptable salt, and a pharmaceutically acceptable carrier or excipient.

The present invention further relates to a method of treating,ameliorating or controlling cancer, including specifically AML,comprising administering to a patient a therapeutically effective amountof a compound according to the invention or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following terms shall have the followingdefinitions.

The terms “C₁₋₆ alkyl” or “C₁₋₄ alkyl” refer to straight- orbranched-chain saturated hydrocarbon groups having from 1 to 6, or 1 to4, carbon atoms, respectively. Examples of C₁₋₆ alkyl groups include,but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkoxy, alkoxyl or lower alkoxy” refers to any of the above alkylgroups which is attached to the remainder of the molecule by an oxygenatom (RO—). Typical alkoxy groups include methoxy, ethoxy, isopropoxy orpropoxy, butyloxy and the like. Further included within the meaning ofalkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxyethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy sidechains, e.g., dimethylamino ethoxy, diethylamino ethoxy,dimethoxy-phosphoryl methoxy and the like.

“Aryl” means a substituted or unsubstituted monovalent, monocyclic orbicyclic, aromatic carboxylic hydrocarbon radical, preferably a 6-10member aromatic ring system. Preferred aryl groups include, but are notlimited to, phenyl, naphthyl, tolyl, and xylyl.

The term “cycloalkyl” as used herein means a substituted orunsubstituted stable monocyclic or polycyclic system which consists ofcarbon atoms only, all rings of which are saturated. Examples ofcycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyls,including bicyclooctanes such as [2.2.2]bicyclooctane or[3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, andbicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spirocompounds.

“Halogen” means Cl, F and Br.

“Heteroaryl” means a substituted or unsubstituted aromatic heterocyclicring system containing up to two rings. Preferred heteroaryl groupsinclude, but are not limited to, thienyl (or thiophenyl), furyl,indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl,quinolinyl, pyrimidinyl, imidazolyl, triazolyl and tetrazolyl.

In the case of a heteroaryl that is bicyclic it should be understoodthat one ring may be aryl while the other is heteroaryl and both may beindependently substituted or unsubstituted.

“Hetero atom” means an atom selected from N, O and S.

“Heterocycle” or “heterocyclic ring” means a substituted orunsubstituted 5 to 10 membered, mono- or bicyclic, non-aromatichydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atomselected from nitrogen, oxygen or sulfur atom. Examples includetetrahydropyran, pyrrolidinyl, including pyrrolidin-1-yl,pyrrolidin-2-yl and pyrrolidin-3-yl; piperazinyl; piperidinyl;morpholinyl, including morpholin-4-yl; and the like, which in turn canbe substituted.

In the case of a heterocycle that is bicyclic it should be understoodthat one ring may be heterocycle while the other is cycloalkyl, andeither or both may be independently substituted. An example of such abicyclic heterocycle is 8-oxa-3-aza-bicyclo[3.2.1]octane.

Hydroxy or hydroxyl is a prefix indicating the presence of a monovalent—O—H group.

“IC₅₀” refers to the concentration of a particular compound required toinhibit 50% of a specific measured activity. IC₅₀ can be measured, interalia, as is described subsequently in Examples 92 and 93.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

“Pharmaceutically acceptable salt” refers to conventional acid-additionsalts or base-addition salts that retain the biological effectivenessand properties of the compounds of the present invention and are formedfrom suitable non-toxic organic or inorganic acids or organic orinorganic bases. Sample acid-addition salts include those derived frominorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, andthose derived from organic acids such as p-toluenesulfonic acid,salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citricacid, malic acid, lactic acid, fumaric acid, trifluoroacetic acid andthe like. Sample base-addition salts include those derived fromammonium, potassium, sodium and, quaternary ammonium hydroxides, such asfor example, tetramethylammonium hydroxide. Chemical modification of apharmaceutical compound (i.e. drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability, hygroscopicity, flowability and solubility ofcompounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems (1995) at pgs. 456-457.

“Substituted,” as in substituted alkyl, means that the substitution canoccur at one or more positions and, unless otherwise indicated, that thesubstituents at each substitution site are independently selected fromthe specified options. The term “optionally substituted” refers to thefact that one or more hydrogen atoms of a chemical group (with one ormore hydrogen atoms) can be, but does not necessarily have to be,substituted with another substituent.

In one embodiment, the present invention relates to compounds of formulaI

wherein

-   X is selected from CH or N,-   R¹ and R² are independently selected from the group consisting of    -   (a) H,    -   (b) C₁₋₄ alkyl,    -   (c) C₁₋₄ alkyl substituted with up to 3 groups selected from        cycloalkyl, heterocycle, OR⁵, NR⁵R⁶, SO₂R⁷ or CN,    -   (d) heterocycle,    -   (e) heterocycle substituted with up to three groups selected        from C₁₋₄ alkyl, OR⁸, NR⁸R⁹ or CN,    -   (f) cycloalkyl, and    -   (g) cycloalkyl substituted with up to three groups selected from        C₁₋₄ alkyl, OR⁸, NR⁸R⁹ or CN; or    -   alternatively, NR¹R² together can be a heterocycle that        optionally may be substituted with C₁₋₄ alkyl;-   R³ is selected from the group consisting of    -   (a) C₁₋₆ alkyl    -   (b) C₁₋₆ alkyl substituted with up to 3 groups selected from        -   aryl,        -   aryl substituted with Cl, F, CH₃, or CF₃,        -   heteroaryl,        -   cycloalkyl,        -   heterocycle,        -   OH,        -   OCH₃,        -   NR⁸R⁹, and        -   CN;    -   (c) aryl,    -   (d) aryl substituted with Cl, F, C₁₋₄ alkyl or CF₃,    -   (e) heteroaryl,    -   (f) cycloalkyl optionally substituted with OR⁵, and    -   (g) heterocycle;-   R⁴, R⁸ and R⁹ are independently selected from the group consisting    of    -   (a) H, and    -   (b) C₁₋₄ alkyl; or-   alternatively, NR³R⁴ together can be a heterocycle that optionally    is substituted with C₁₋₄ alkyl;-   R⁵ and R⁶ are independently selected from the group consisting of    -   (a) H, and    -   (b) C₁₋₄ alkyl; and-   R⁷ is selected from the group    -   (a) C₁₋₄ alkyl, and    -   (b) cycloalkyl;-   or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula Iahaving the structure

wherein R¹, R², R³ and R⁴ are as defined above, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the invention relates to compounds of formula Ibhaving the structure

wherein R¹, R², R³ and R⁴ are as defined above, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is C₁₋₄ alkyl, ora pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is C₁₋₄ alkyl thatoptionally is substituted with a heterocycle, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is C₁₋₄ alkyl thatoptionally is substituted with OR⁵, including specifically OH, or apharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is C₁₋₄ alkyl thatoptionally is substituted with SO₂R⁷, or a pharmaceutically acceptablesalt thereof. In an embodiment R⁷ is C₁₋₄ alkyl, specifically methyl, ora pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is cycloalkyl, ora pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is cycloalkyl thatis substituted with NR⁸R⁹, including specifically NH₂, or apharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to compounds of formula I,including compounds of formulas Ia and Ib, wherein R¹ is heterocycle,including specifically piperidine and morpholine, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ is as definedimmediately above and R² is H, or a pharmaceutically acceptable saltthereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ is as definedimmediately above and R² is C₁₋₄ alkyl, or a pharmaceutically acceptablesalt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, NR¹R² together are aheterocycle, including specifically piperazine, that optionally may besubstituted with C₁₋₄ alkyl, including specifically methyl, or apharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and R³ is C₁₋₆ alkyl, specifically C₁₋₄ alkyl,or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and R³ is C₁₋₄ alkyl that is substituted withup to 2 groups selected from NH₂, thiophene and phenyl, or apharmaceutically acceptable salt thereof. The phenyl group optionallymay substituted with Cl.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and R³ is cycloalkyl, including specificallycyclohexane, that optionally may be substituted with OH, or apharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and R³ is aryl, including specifically phenyl,or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and R³ is heterocycle, specificallytetrahydropyran or morpholine, or a pharmaceutically acceptable saltthereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹, R² and R³ are asdefined immediately above and R⁴ is H, or a pharmaceutically acceptablesalt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹ and R² are asdefined immediately above and NR³R⁴ together form a heterocycle,including specifically morpholine and piperazine, said heterocycleoptionally being substituted by C₁₋₄ alkyl, including specificallymethyl, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹, R², R³ and R⁴ areas defined immediately above and R⁵ and R⁶ are independently H or CH₃,or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula I,including compounds of formulas Ia and Ib, wherein R¹, R², R³, R⁴, R⁵and R⁶ are as defined immediately above and R⁷, R⁸ and R⁹ areindependently selected from a C₁₋₄ alkyl group, including specificallymethyl, or a pharmaceutically acceptable salt thereof.

It is contemplated herein that salts of compounds of formula I such ashydrochloride or trifluoroacetic acid salts include salts with multipleconjugates such as mono HCl, di-HCl, etc.

Compounds according to the invention include:

-   Isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 12);-   2-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol    (Example 13);-   (2-Methanesulfonyl-ethyl)-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine    (Example 14);-   (2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 15);-   [3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-amine    (Example 16);-   4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol    (Example 17);-   Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine    (Example 18);-   Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 19);-   Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 20);-   Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 21);-   Piperidin-4-yl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine    (Example 22);-   [3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine    (Example 23);-   [3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine    (Example 24);-   Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 25);-   [3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine    (Example 26);-   4-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanol    (Example 27);-   2-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanol    (Example 28);-   2-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol    (Example 29);-   2-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol    (Example 30);-   2-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol    (Example 31);-   Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 32);-   (2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 33);-   Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine    (Example 34);-   Methyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine    (Example 35);-   N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine;    hydrochloride (Example 52);-   N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine;    hydrochloride (Example 54);-   N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine;    hydrochloride (Example 55);-   Benzyl-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine    (Example 56);-   Benzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine    (Example 57);-   (2-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;    hydrochloride (Example 58);-   (4-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;    hydrochloride (Example 59);-   N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine;    hydrochloride (Example 60);-   {4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine    (Example 61);-   1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine;    hydrochloride (Example 63);-   {4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine;    hydrochloride (Example 64);-   (2-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;    hydrochloride (Example 65);-   (3-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;    hydrochloride (Example 66);-   N-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 67);-   N-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;    hydrochloride (Example 68);-   N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine;    hydrochloride (Example 70);-   (4-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;    hydrochloride (Example 71);-   [3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;    hydrochloride (Example 72);-   N-[3-(6-Benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;    hydrochloride (Example 73);

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine;hydrochloride (Example 75);

-   N-{3-[2-(3-Amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 76);-   N-{3-[2-(2-Amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 77);-   1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine;    hydrochloride (Example 79);-   N-{3-[6-(2-Amino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 80);-   N-{3-[6-(3-Amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 81);-   N-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 82);-   N-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 83);-   N-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;    hydrochloride (Example 84);-   N-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 85);-   N-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;    hydrochloride (Example 86);-   N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;    hydrochloride (Example 87);-   {3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;    hydrochloride (Example 88);-   {3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;    hydrochloride (Example 89);-   1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diamine    hydrochloride (Example 90); and-   1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diamine    hydrochloride (Example 91);    and the pharmaceutically acceptable salts of the foregoing    compounds.

The compounds of formula I, as well as their salts, that have at leastone asymmetric carbon atom may be present as racemic mixtures ordifferent stereoisomers. The various isomers can be isolated by knownseparation methods, e.g., chromatography.

Compounds disclosed herein and covered by formula I above may exhibittautomerism or structural isomerism. It is intended that the inventionencompasses any tautomeric or structural isomeric form of thesecompounds, or mixtures of such forms, and is not limited to any onetautomeric or structural isomeric form depicted in the formulas above.

Dosages

The compounds of the present invention are inhibitors of FLT3 and areuseful in the treatment, amelioration or control of cell proliferativedisorders, in particular chemoprevention of cancer. Chemoprevention isdefined as inhibiting the development of invasive cancer by eitherblocking the initiating mutagenic event or by blocking the progressionof pre-malignant cells that have already suffered an insult ofinhibiting tumor relapse. These compounds and formulations containingsaid compounds are anticipated to be particularly useful in thetreatment or control of acute myeloid leukemia (AML).

A “therapeutically effective amount” or “effective amount” of a compoundin accordance with this invention means an amount of compound that iseffective to alleviate, ameliorate or control symptoms of disease orprolong the survival of the subject being treated.

The therapeutically effective amount or dosage of a compound accordingto this invention can vary within wide limits. Such dosage will beadjusted to the individual requirements in each particular caseincluding the specific compound(s) being administered, the route ofadministration, the condition being treated, as well as the patientbeing treated. In general, in the case of oral or parenteraladministration to adult humans weighing approximately 70 Kg, a dailydosage of about 10 mg to about 10,000 mg, preferably from about 200 mgto about 1,000 mg, should be appropriate, although the upper limit maybe exceeded when indicated. The daily dosage can be administered as asingle dose or in divided doses, or for parenteral administration; itmay be given as continuous infusion.

Compositions/Formulations

In an alternative embodiment, the present invention includespharmaceutical compositions comprising at least one compound of formulaI, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient and/or carrier.

These pharmaceutical compositions can be suitable for oral, nasal,topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, as well as the particularmode of administration. The amount of active ingredient which can becombined with a carrier material to produce a single dosage form willgenerally be that amount of a formula I compound which produces atherapeutic effect. Generally, out of one hundred percent, this amountwill range from about 1 percent to about ninety-nine percent of activeingredient, preferably from about 5 percent to about 70 percent, mostpreferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, sachets, pills, tablets, lozenges (usinga flavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

The pharmaceutical preparations of the invention can also containpreserving agents, solubilizing agents, stabilizing agents, wettingagents, emulsifying agents, sweetening agents, coloring agents,flavoring agents, salts for varying the osmotic pressure, buffers,coating agents or antioxidants. They can also contain othertherapeutically valuable substances, including additional activeingredients other than those of formula I.

General Synthesis of the Compounds According to the Invention

The present invention also provides methods for the synthesis ofimidazol[1,2-a]pyrazines of the invention.

The compounds of the invention can be prepared by processes known in theart. Suitable processes for synthesizing these compounds are alsoprovided in the examples. Generally, compounds of formula I can besynthesized according to one of the below described synthetic routes.

The starting materials are either commercially available or can besynthesized by methods known in the art. Compounds of formula Ia where Xis N can be synthesized starting from the known3-bromo-8-chloro-imidazo[1,2-a]pyrazine (4). Lumma, Jr., W. C.; Randall,W. C.; Cresson, E. L.; Huff, J. R.; Hartman, R. D.; Lyon, T. F. J. Med.Chem. 1983, 26, 357-363. Meurer, L. C.; Tolman, R. L.; Chapin, E. W.;Saperstein, R.; Vicario, P. P.; Zrada, M. M.; MacCoss, M. J. Med. Chem.1992, 35, 3845-3857. In accordance to Scheme 1 below,2-amino-3-chloropyrazine (1) can be reacted with2-bromo-1,1-dimethoxy-ethane (2) to give 8-chloro-imidazo[1,2-a]pyrazine(3) which can be brominated to give3-bromo-8-chloro-imidazo[1,2-a]pyrazine (4). Compound 4 can be reactedwith an appropriate amine (HNR¹R²) either in excess or in the presenceof another base, such as diisopropyl ethyl amine, in an appropriatesolvent, such as ethanol or butanol, between room temperature to refluxto give compound 5. Compound 5 can than be condensed with2-methylsulfanyl-4-tributylstannanyl-pyrimidine (6) in the presence of asuitable palladium catalyst to give intermediate 7.

In cases of certain amines that contained additional functional groups,appropriate protecting groups (for example tert-butoxy-carbonyl group)may be employed to facilitate synthesis. If such protecting groups areemployed, the removal of such protecting groups to generate thecompounds of the invention can be accomplished by standard methods knownto those skilled in the art of organic synthesis.

Alternatively, intermediate 7 used in the synthesis of compounds offormula Ia can be prepared according to Schemes 2-4 below.2-Methylsulfanyl-pyrimidine-4-carbaldehyde (8) can be condensed with(methoxymethyl)triphenylphosphonium chloride (Wittig reaction) to give4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine (9). Oxidation of (9)with N-bromosuccinimide in methanol provides4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (10).Condensation of (10) with 2-amino-3-chloropyrazine (1) in aqueous acidand a co-solvent such as acetone gives8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine(11). Compound 11 can then be reacted with an appropriate amine (HNR¹R²)either in excess or in the presence of another base, such as diisopropylethyl amine, in an appropriate solvent, such as ethanol or butanol,between room temperature to reflux to give the intermediate 7.Intermediate 7 can also be prepared via the ethyl homologs 9′ and 10′according to Scheme 4 below. Compound 9′ (the ethyl homolog) can beprepared by the reaction ethyl ethynyl ether (13) withborane—tetrahydrofuran complex followed by palladium catalyzed couplingwith 4-chloro-2-(methylthio)pyrimidine (12). Oxidation of 9′ withN-bromosuccinimide in ethanol provides the ethyl homolog 10′. Homolog10′ can be converted to intermediate 7 in the same way as 10.

Intermediate 7 can be converted to compounds Ia of this invention byfollowing Scheme 5 below. After oxidation with a suitable oxidant, suchas a per acid or Oxone, to give either the sulfoxide (14, n=1) orsulfone (14, n=2), the resulting sulfoxide or sulfone 14 can beconverted to compounds Ia of this invention by heating it with theappropriate amine (HNR³R⁴).

Compounds Ib of this invention can be prepared in a sequence analogousto that for compounds Ia as outlined below in Scheme 6-7. Starting from6-bromo-pyridine-2-carbaldehyde (15) instead of the pyrimidine analog 8,the corresponding intermediate 19 can be prepared. Intermediate 19 canthen be converted to compounds Ib of this invention via a palladiumcatalyzed reaction with the appropriate amine (HNR³R⁴).

Crystal Forms

When the compounds of the invention are solids, it is understood bythose skilled in the art that these compounds, and their salts, mayexist in different crystal or polymorphic forms, all of which areintended to be within the scope of the present invention and specifiedformulas.

EXAMPLES

The compounds of the present invention may be synthesized according toknown techniques. The following examples and references are provided toaid the understanding of the present invention. The examples are notintended, however, to limit the invention, the true scope of which isset forth in the appended claims. The names of the final products in theexamples were generated using AutoNom 2000 Add-in v4.0 SP2, (function inISIS Draw, Elsevier/MDL), or AutoNom 2000 TT v4.01.305 (Elsevier/MDL),or functions available in ChemDraw Pro Control 11.0.2 (CambridgeSoftCorp.).

Abbreviations Used In The Examples

-   ATP adenosine triphosphate-   Boc₂O di-tert-butyl dicarbonate-   ^(n)BuOH n-butanol-   CDCl₃ chloroform-d-   CD₃OD deuterated methanol-   CH₂Cl₂ dichloromethane-   CH₃CN acetonitrile-   CH₃OH methanol-   CO₂ carbon dioxide-   DCM dichloromethane-   DEAD diethyl azodicarboxylate-   DIPE diisopropyl ether-   DIPEA N,N-diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ deuterated dimethylsulfoxide-   Et₃N triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   FBS fetal bovine serum-   HCl hydrogen chloride-   Concentrated HCl concentrated hydrochloric acid-   H₂O water-   HPLC high performance liquid chromatography-   iPrOH 2-propanol-   LAH lithium aluminum hydride-   LC-MS liquid chromatography-mass spectroscopy-   LDA lithium diisopropylamide-   LiAlH₄ lithium aluminum hydride-   KCN potassium cyanide-   K₂CO₃ potassium carbonate-   mCPBA meta-chloro-perbenzoic acid-   MeCN acetonitrile-   MeOH methanol-   MgCl₂ magnesium chloride-   MgSO₄ magnesium sulfate-   N₂ nitrogen gas-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   NaOtBu sodium t-butoxide-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   PPh₃ triphenylphosphine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography

The following starting materials were purchased from the sources listedbelow.

-   LDA Sigma-Aldrich (Shanghai) Trading Co., Ltd-   Ethyl ethynyl ether Alfa Aesar China (Tianjin) Co., Ltd.-   borane tetrahedrofuran Alfa Aesar China (Tianjin) Co., Ltd.-   Oxone Beijing huaxue shiji-   (Methoxymethyl)triphenylphosphonium chloride Alfa Aesar China    (Tianjin) Co., Ltd.-   4-chloro-2-(methylthio)pyrimidine Alfa Aesar China (Tianjin) Co.,    Ltd.-   1,1′-Bis(diphenylphosphino)ferrocene Shanghai Aopudishi-   2-dicyclohexylphosphino-2(N,N-dimethylamino)biphenyl Alfa Aesar    China (Tianjin) Co., Ltd.-   X-Phos Alfa Aesar China (Tianjin) Co., Ltd.-   1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium Shanghai    Aopudishi-   2-Amino-3-chloropyrazine Alfa Aesar China (Tianjin) Co., Ltd.-   2-Chlorobenzylamine Alfa Aesar China (Tianjin) Co., Ltd.-   3-Chlorobenzylamine Alfa Aesar China (Tianjin) Co., Ltd.-   4-Chlorobenzylamine Alfa Aesar China (Tianjin) Co., Ltd.-   2-Thiophenemethylamine Alfa Aesar China (Tianjin) Co., Ltd.-   2-Methylsulfanyl-pyrimidine-4-carbaldehyde Alfa Aesar China    (Tianjin) Co., Ltd.-   4-(2-Aminoethyl)morpholine Alfa Aesar China (Tianjin) Co., Ltd.-   Triphenylphosphine Beijing huaxue shiji-   N-Bromosuccinimide Beijing Ouhe-   3-Chloroperoxybenzoic acid Beijing Ouhe-   Phosphorus oxychloride Beijing Huagong-   p-Toluenesulfonic acid Beijing Huagong-   2-(Methylthio)-4-(tributylstannyl)pyrimidine Alfa Aesar

Example 1 3-Bromo-8-chloro-imidazo[1,2-a]pyrazine

3-Bromo-8-chloro-imidazo[1,2-a]pyrazine was prepared according to theprocedures of Lumma, Jr., W. C.; Randall, W. C.; Cresson, E. L.; Huff,J. R.; Hartman, R. D.; Lyon, T. F. J. Med. Chem. 1983, 26, 357-363.Meurer, L. C.; Tolman, R. L.; Chapin, E. W.; Saperstein, R.; Vicario, P.P.; Zrada, M. M.; MacCoss, M. J. Med. Chem. 1992, 35, 3845-3857.

Example 2 2-(3-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol

3-Bromo-8-chloro-imidazo[1,2-a]pyrazine (0.70 g, 3.0 mmol) (from Example1 supra) was stirred in ^(n)BuOH (10 mL) and ethanolamine (0.22 mL, 3.65mmol) followed by Hunig's base (1.04 mL, 6.0 mmol) Reaction mixture wasthen heated at 100° C. overnight. The mixture was concentrated todryness and water was added (150 mL) followed by a saturated aqueoussolution of NaHCO₃ (50 mL). The reaction was then extracted with EtOAc(3×20 mL) and the organic phases were combined, washed with water (2×20mL), dried over MgSO₄ and concentrated to dryness to give2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol. (Yield 0.59 g,77%). ¹H (400 MHz; DMSO-d₆) δ 3.52-3.56 (2 H, m), 3.58-3.62 (2 H, m),4.79 (1 H, t, J=5.4 Hz), 7.42 (2 H, d, J=5 Hz), 7.56 (1 H, d, J=5 Hz),7.66 (1 H, s).

Example 3(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-amine

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-amine wasprepared by a process analogous to that described in Example 2 startingfrom 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and2-methylsulfanyl-ethylamine.

Example 4(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-carbamicacid tert-butyl ester

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-amine(1.33 g, 4.63 mmol) (from Example 3 supra) was stirred in 1,4-dioxane(30 mL) and Boc₂O (1.00 g, 4.63 mmol) followed by DMAP (30 mg, 0.25mmol) were added and the reaction was heated at 90° C. for 5 hours.After this time, additional Boc₂O (1.00 g, 4.63 mmol) was added and thereaction was stirred at 90° C. overnight. The reaction was concentratedto dryness and Et₂O (50 mL) added. The organic layer was washed withwater (4×25 mL), dried over MgSO₄ and concentrated to dryness. The crudeproduct was purified by column chromatography on silica gel (100%petroleum ether to 40% EtOAc in petroleum ether, TLC R_(f)=0.52, 30%EtOAc in petroleum ether) to give(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-carbamicacid tert-butyl ester. (Yield 1.15 g, 64%). ¹H (400 MHz; CDCl₃) δ 1.41(9 H, s); 2.10 (3 H, s); 2.85-2.89 (2 H, m), 4.07-4.11 (2 H, m), 7.75 (1H, s), 7.81 (1 H, d, J=5 Hz), 7.95 (1 H, d, J=5 Hz).

Example 5(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-carbamicacid tert-butyl ester (1.52 g, 3.93 mmol) (from Example 4 supra) wasstirred in DCM (25 mL), cooled in ice and mCPBA (2.20 g, 77% max purity,9.82 mmol) added portion-wise over 3 minutes. The reaction was stirredfor 30 minutes then diluted with DCM (50 mL) and washed with 10% sodiummetabisulphite (25 mL), 10% NaHCO₃ (3×25 mL), dried over MgSO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (petroleum ether to EtOAc; TLC R_(f)=0.23,60% EtOAc in petroleum ether) to give(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester. (Yield 1.61 g, 98%).

¹H (400 MHz; CDCl₃) δ 1.40 (9 H, s), 3.04 (3 H, s), 3.61 (2 H, t, J=7Hz), 4.31-4.35 (2 H, m), 7.74 (1 H, s), 7.83 (1 H, d, J=5 Hz), 7.99 (1H, d, J=5 Hz).

Example 6 (3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine was prepared by aprocess analogous to that described in Example 2 starting from3-bromo-8-chloro-imidazo[1,2-a]pyrazine and excess methylamine (33%weight in EtOH) at room temperature in EtOH.

Example 7 (3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-carbamic acidtert-butyl ester

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-carbamic acid tert-butylester was prepared by a process analogous to that described in Example 4starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (fromExample 6 supra).

Example 8Methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester

2-Methylsulfanyl-4-tributylstannanyl-pyrimidine (19.1 g, 46.0 mmol) wasstirred in degassed toluene (achieved by bubbling nitrogen thoughsolvent for 2 hours) (200 mL) under nitrogen, then(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-carbamic acid tert-butylester (13.1 g, 40.0 mmol) (from Example 7 supra) was added followed bybis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.60 mmol) andthe reaction was heated at reflux. The reaction was cooled to roomtemperature and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel (petroleum ether to EtOAc, TLCR_(f)=0.17, 20% EtOAc in petroleum ether) and then triturated with DIPEto givemethyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester. (Yield 8.00 g, 54%).

-   ¹H (400 MHz; CDCl₃) δ 1.42 (9 H, s), 2.67 (3 H, s), 3.48 (3 H, s),    7.36 (1 H, d, J=4 Hz), 7.93 (1 H, d, J=4 Hz), 8.37 (1 H, s), 8.55 (1    H, d, J=4 Hz), 9.64 (1 H, d, J=4 Hz). LC-MS: [M+H]⁺373.3.

Example 9 (3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-amine

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-amine was prepared by aprocess analogous to that described in Example 2 starting from3-bromo-8-chloro-imidazo[1,2-a]pyrazine and isopropylamine.

Example 10 (3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-carbamic acidtert-butyl ester

(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-carbamic acid tert-butylester was prepared by a process analogous to that described in Example 4starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-amine (fromExample 9 supra).

Example 11Isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester

Isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester was prepared by a process analogous to thatdescribed in Example 8 starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-carbamic acid tert-butylester (from Example 10 supra).

Example 12Isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Toisopropyl-[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (117 mg, 0.27 mmol) (from Example 11 supra) wasadded aniline (38 μL, 0.42 mmol) in ^(n)BuOH (3 mL) followed by conc.HCl(38 μL, 0.46 mmol) and the reaction was shaken at 95° C. overnight.After this time the reaction was concentrated to dryness, dissolved inDMSO (1.8 mL) and then purified by preparative HPLC to giveisopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine.(Yield 27.3 mg, 29%). LC-MS: [M+H]⁺ 346.3.

Example 132-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol

2-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanolwas prepared by a process analogous to that described in Example 12starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (fromExample 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, andaniline. LC-MS: [M+H]⁺ 348.3.

Example 14(2-Methanesulfonyl-ethyl)-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine

(2-Methanesulfonyl-ethyl)-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-aminewas prepared by a process analogous to that described in Example 12starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester (from Example 5 supra),2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and4-amino-tetrahydropyran. LC-MS: [M+H]⁺ 418.2.

Example 15(2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

(2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester (from Example 5 supra),2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and morpholine. LC-MS:[M+H]⁺ 404.2.

Example 16[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-amine

[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-aminewas prepared by a process analogous to that described in Example 12starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester (from Example 5 supra),2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and isopropylamine.LC-MS: [M+H]⁺ 376.3.

Example 174-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol

4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanolwas prepared by a process analogous to that described in Example 12starting fromisopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 11 supra), andtrans-4-amino-cyclohexanol. LC-MS: [M+H]⁺ 368.3.

Example 18Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine

Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-aminewas prepared by a process analogous to that described in Example 12starting fromisopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 11 supra), and4-amino-tetrahydropyran. LC-MS: [M+H]⁺ 354.3.

Example 19Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting fromisopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 11 supra), and morpholine. LC-MS:[M+H]⁺ 340.3.

Example 20Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting frommethyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 8 supra), and aniline. LC-MS: [M+H]⁺318.2.

Example 21Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting frommethyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 8 supra), and morpholine. LC-MS:[M+H]⁺ 312.3.

Example 22Piperidin-4-yl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine

Piperidin-4-yl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-aminewas prepared by a process analogous to that described in Example 12starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (from Example 1supra), 4-amino-piperidine-1-carboxylic acid tert-butyl ester,2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and4-amino-tetrahydropyran. LC-MS: [M+H]⁺ 395.4.

Example 23[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine

[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-aminewas prepared by a process analogous to that described in Example 12starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (from Example 1supra), 4-amino-piperidine-1-carboxylic acid tert-butyl ester,2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and morpholine. LC-MS:[M+H]⁺ 381.3.

Example 24[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine

[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-aminewas prepared by a process analogous to that described in Example 12starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (from Example 1supra), 4-amino-piperidine-1-carboxylic acid tert-butyl ester,2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and isopropylamine.LC-MS: [M+H]⁺ 353.3.

Example 25

Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting fromisopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 11 supra), and isopropylamine.LC-MS: [M+H]⁺ 312.3.

Example 26[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine

[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-aminewas prepared by a process analogous to that described in Example 12starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (from Example 1supra), 4-amino-piperidine-1-carboxylic acid tert-butyl ester,2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and methylamine. LC-MS:[M+H]⁺ 325.3.

Example 274-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanol

4-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanolwas prepared by a process analogous to that described in Example 12starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester (from Example 5 supra),2-methylsulfanyl-4-tributylstannanyl-pyrimidine, andtrans-4-amino-cyclohexanol. LC-MS: [M+H]⁺ 432.1.

Example 282-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanol

2-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanolwas prepared by a process analogous to that described in Example 12starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (fromExample 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and4-amino-tetrahydropyran. LC-MS: [M+H]⁺ 356.3.

Example 292-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol

2-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanolwas prepared by a process analogous to that described in Example 12starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (fromExample 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, andmorpholine. LC-MS: [M+H]⁺ 342.3.

Example 302-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol

2-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanolwas prepared by a process analogous to that described in Example 12starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (fromExample 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, andisopropylamine. LC-MS: [M+H]⁺ 314.3.

Example 312-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol

2-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanolwas prepared by a process analogous to that described in Example 12starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (fromExample 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, andmethylamine. LC-MS: [M+H]⁺ 286.2.

Example 32Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting fromisopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 11 supra), and methylamine.

LC-MS: [M+H]⁺ 284.3.

Example 33(2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

(2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting from(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamicacid tert-butyl ester (from Example 5 supra),2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and methylamine. LC-MS:[M+H]⁺ 348.2.

Example 34Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine

Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-aminewas prepared by a process analogous to that described in Example 12starting frommethyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 8 supra), and4-amino-tetrahydropyran.

LC-MS: [M+H]⁺ 326.3.

Example 35Methyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine

Methyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-aminewas prepared by a process analogous to that described in Example 12starting frommethyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamicacid tert-butyl ester (from Example 8 supra), and methylamine LC-MS:[M+H]⁺ 256.2.

Example 36 2-Bromo-6-(-2-methoxy-vinyl)-pyridine

To a suspension of (methoxymethyl)triphenylphosphonium chloride (34.5 g,100.6 mmol) in THF (500 mL) at −10° C. was added LDA (60 mL, 2 mol/L).The mixture was stirred at −10° C. for 1 hour before addition of6-bromopicolinaldehyde (10 g, 53.8 mmol) in THF (200 mL). The reactionmixture was then allowed to warm to room temperature and stirred at roomtemperature for 12 hours. The solution was then partitioned betweenwater and ether. The aqueous fraction was separated and extracted twicewith ether. The organic layers were washed with brine and dried overNa₂SO₄ and filtered. The filtrate was concentrated under reducedpressure to give the crude product which was purified by chromatography(petroleum ether:ethyl acetate, 20:1) to give2-bromo-6-(-2-methoxy-vinyl)-pyridine. (Yield 9.3 g, 80%). LC-MS: [M+H]⁺215.

Example 37 2-Bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine

2-Bromo-6-(-2-methoxy-vinyl)-pyridine (from Example 36 supra) (9.3 g,43.4 mmol) was dissolved in methanol (200 mL), and NBS (9.3 g, 52.3mmol) was added to the solution at 0° C. After stirring at the sametemperature for 30 minutes, water was added to the mixture. The obtainedreaction solution was extracted with ethyl acetate. The organic layerwas washed with brine, dried and filtered. The filtrate was concentratedunder reduced pressure to give a residue which was purified bychromatography (petroleum ether:ethyl acetate, 20:1) to give2-bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine. (Yield 11.9 g, 84%).LC-MS: [M+H]⁺ 324.

Example 38 3-(6-Bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine

A mixture of 2-bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine (fromExample 37 supra) (5.267 g, 16.2 mmol), 3-chloropyrazin-2-amine (2.1 g,16.2 mmol), and pTsOH.H₂O (2.1 g, 11 mmol) in CH₃CN (900 mL) and water(90 mL) was stirred and heated at reflux overnight. The reaction mixturewas then cooled to room temperature, concentrated under reducedpressure. The crude product was purified by chromatography(CH₂Cl₂:CH₃OH, 100:1) to give3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine. (Yield 4.86 g,52%). LC-MS: [M+H]⁺ 309.

Example 393-(6-Bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine

A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine(from Example 38 supra) (1.44 g, 4.65 mmol), 1-methylpiperazine (2.1 g,21 mmol), and diisopropylethylamine (2.7 g, 21 mmol) in 2-propanol (300mL) was stirred and heated at reflux overnight. The solution was thencooled to room temperature, concentrated under reduced pressure. Theresulted solid was washed with water, partitioned between CH₂Cl₂ andbrine. The organic layer was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure. The crude product waspurified by chromatography (CH₂Cl₂:CH₃OH, 100:1) to give3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine.(Yield 1.27 g, 73%).

LC-MS: [M+H]⁺ 373.

Example 40{4-[3-(6-Bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester

A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine(from Example 38 supra) (1.94 g, 6.27 mmol),trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.61 g, 7.52mmol), K₂CO₃ (1.04 g, 7.52 mmol) in DMF (20 mL) was stirred at 140° C.for 15 hours. The solution was then cooled to room temperature andpoured into water.

The resulted solid was filtered and washed with water. The crude productwas purified by chromatography (CH₂Cl₂:CH₃OH, 100:1) to give{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester. (Yield 0.512 g, 17%). LC-MS: [M+H]⁺ 487.

Example 41[3-(6-Bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine

A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine(from Example 38 supra) (3.09 g, 10.0 mmol), 2-morpholin-4-yl-ethylamine(2.6 g, 20.0 mmol), NEt₃ (2.02 g, 20.0 mmol) in 2-propanol (300 mL) wasstirred and heated at reflux for 16 hours. The solution was then cooledto room temperature and poured into water. The resulted solid wasfiltered and washed with water. The crude product was purified bychromatography (CH₂Cl₂:CH₃OH, 20:1) to give[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine.(Yield 2.5 g, 62%). LC-MS: [M+H]⁺ 403.

Example 42 4-(2-Methoxy-vinyl)-2-methylsulfanyl-pyrimidine

(Methoxymethyl)triphenylphosphonium chloride (68.6 g, 0.2 mol) wasdissolved in THF (1000 mL), and lithium diisopropylamide (100 mL, 0.2mol) was added to the solution at −20° C. After stirring at roomtemperature for 0.5 hour, the solution of2-(methylthio)pyrimidine-4-carbaldehyde (15.4 g, 0.1 mol) in THF (400mL) was added to the solution dropwise. The reaction mixture was stirredat room temperature overnight. Then saturated aqueous ammonium chloridesolution (200 mL) was added to the mixture, extracted with ethyl acetate(1500 mL), and dried over with anhydrous sodium sulfate. The organiclayer was concentrated and purified by chromatography (petroleumether:ethyl acetate, 3:1) to give4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine as a yellow solid.(Yield 11.2 g, 61.2%). LC-MS: [M+H]⁺ 183.

Example 43 4-(1-Bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine

To a stirred solution of 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine(from Example 42 supra) (11.2 g, 61.2 mmol) in methanol (100 mL) wasadded N-bromosuccinimide (12 g, 67.3 mmol) at 0° C. After stirring atroom temperature for 1 hour, water (100 mL) was added to the mixture,extracted with ethyl acetate (200 mL), and the organic layer dried overwith anhydrous sodium sulfate and filtered. Then the filtrate wasconcentrated and purified by chromatography (petroleum ether:ethylacetate, 5:1) to give4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine as a yellowoil. (Yield 11.5 g, 64.1%). LC-MS: [M+H]⁺ 293.

Example 448-Chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine

The mixture of4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (fromExample 43 supra) (7.5 g, 25.6 mmol), 3-chloropyrazin-2-amine (3.96 g,30.7 mmol) and p-toluenesulfonic acid (1.594 g, 9.22 mmol) in the mixsolvent of acetonitrile/water (120 mL:6 mL) was heated at reflux for 6hours. The reaction mixture was concentrated and purified bychromatography (dichloromethane:methanol, 20:1) to give8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine as awhite solid. (Yield 2.3 g, 32.4%). LC-MS: [M+H]⁺ 278.

Example 458-(4-Methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine

To a solution of8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine(from Example 44 supra) (1.36 g, 4.91 mmol) in iPrOH (100 mL) was added1-methylpiperazine (0.64 g, 6.38 mmol) followed by diisopropylethylamine(0.82 g, 6.38 mmol). The reaction mixture was stirred at reflux for 15hours and the solvent was removed under reduced pressure. The residuewas extracted with dichloromethane (150 mL) and washed with water (3×25mL), dried over anhydrous sodium sulfate, filtered, and concentrated toafford8-(4-methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine.(Yield 1.4 g, 83.7%). LC-MS: [M+H]⁺ 342.

Example 463-(2-Methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine

8-(4-Methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine(from Example 45 supra) (0.9 g, 2.64 mmol) was dissolved indichloromethane (40 mL), m-CPBA (1.07 g, 5.28 mmol) was added slowly.The reaction mixture was stirred at 0° C. for 2 hours. Solvent wasremoved under reduced pressure and the solid was purified by columnchromatography (silica, 20 g, 200˜300 mesh, eluting withdichloromethane:methanol, 1:1) to afford3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine.(Yield 0.9 g, 91.4%). LC-MS: [M+H]⁺ 374.

Example 47{4-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester

To a solution of8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine(from Example 44 supra) (0.9 g, 3.24 mmol) in DMF (25 mL) was addedtrans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.04 g, 4.86mmol) followed by diisopropylethylamine (0.63 g, 4.86 mmol). Thereaction mixture was stirred at 95° C. for 15 hours and the mixture waspoured into water. The precipitate formed was filtered, and. theobtained solid was purified by chromatography (silica gel, 10 g, 200-300mesh, eluting with dichloromethane:methanol, 50:1) to afford{4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester. (Yield 1.23 g, 83.4%). LC-MS: [M+H]⁺ 456.

Example 48{4-[3-(2-Methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester

{4-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 47 supra) (150 mg, 0.323 mmol) wasdissolved in dichloromethane (20 mL), then m-CPBA (134 mg, 0.659 mmol)was added slowly. The reaction mixture was stirred at 0° C. for 2 hours.The solvent was removed under reduced pressure and the solid waspurified by chromatography (silica gel, 10 g, 200-300 mesh, eluting withdichloromethane:methanol, 20:1) to afford{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester. (Yield 110 mg, 70.8%). LC-MS: [M+H]⁺ 472.

Example 49[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine

To a solution of8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine(from Example 44 supra) (400 mg, 1.44 mmol) in iPrOH (20 mL) was added2-morpholino-ethanamine (244 mg, 1.88 mmol) followed bydiisopropylethylamine (242 mg, 1.88 mmol). The reaction mixture wasstirred at reflux for 15 hours and the solvent was removed under reducedpressure. The residue was extracted with dichloromethane (150 mL) andwashed with water (3×25 mL), dried over anhydrous sodium sulfate andconcentrated to afford[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine.(Yield 410 g, 76.8%). LC-MS: [M+H]⁺ 372.

Example 50[3-(2-Methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine

[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 49 supra) (410 mg, 1.11 mmol) was dissolved indichloromethane (20 mL). m-CPBA (449 mg, 2.21 mmol) was added slowly.The reaction mixture was stirred at 0° C. for 2 hours. Solvent was thenremoved under reduced pressure and the solid was purified by columnchromatography (silica gel, 10 g, 200-300 mesh, eluting withdichloromethane:methanol, 1:3) to afford[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine.(Yield 300 mg, 67.4%). LC-MS: [M+H]⁺ 404.

Example 51 (2-Amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester

(2-Amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester was preparedaccording to the literature procedure of Seefeld, M. A.; Rouse, M. B.;Heerding, D. A.; Peace, S.; Yamashita, D. S.; McNulty, K. C. WO2008/098104, Aug. 14, 2008.

Step A

(2-Hydroxy-2-phenyl-ethyl)-carbamic acid tert-butyl ester

To a stirred solution of 2-amino-1-phenylethanol (20 g, 145.8 mmol) inTHF (300 mL) was added the solution of Boc₂O (31.1 g, 153.1 mmol) in THF(100 mL) at 0° C. After addition, the mixture was stirred at roomtemperature for 0.5 hour. This mixture was concentrated to give the pure(2-hydroxy-2-phenyl-ethyl)-carbamic acid tert-butyl ester as a whitesolid. (Yield 34.4 g, 100%).

Step B

[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acidtert-butyl ester

To a solution of (2-hydroxy-2-phenyl-ethyl)-carbamic acid tert-butylester (34.4 g, 145.0 mmol), phthalimide (21.3 g, 145 mmol), and PPh₃(49.4 g, 188.5 mmol) was added drop-wise DEAD (32.8 g, 188.5 mmol) understirring at 0° C. After addition, the mixture was stirred at roomtemperature for an additional 1 hour. The mixture was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (petroleum ether:ethyl acetate, 20:1 to 5:1) to give[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acidtert-butyl ester as a white solid. (Yield 39 g, 74%) ¹H NMR (300 MHz,CDCl₃): δ 7.88-7.80 (m, 2H), 7.74-7.68 (m, 2H), 7.49-7.47 (m, 2H),7.38-7.26 (m, 3H), 5.56-5.50 (m, 1H), 4.83 (brs, 1H), 4.28-4.22 (m, 1H),3.93-3.87 (m, 1H), 1.35 (s, 9H). LC-MS: [M-Boc+H]⁺ 267.

Step C

(2-Amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester

To a solution of[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acidtert-butyl ester (23 g, 63 mmol) in THF (180 mL) and MeOH (180 mL) wasadded 85% hydrazine hydrate (37 mL, 630 mmol) slowly. The resultingmixture was heated to 65° C. for 15 hours. The reaction mixture wascooled to room temperature, then concentrated to dryness. The residuewas purified by column chromatography on silica gel(dichloromethane:MeOH, 100:1, 1% NH₃ H₂O) to give(2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester as a whitesolid. (Yield 7.4 g, 50%). ¹H NMR (300 MHz, CDCl₃): δ 7.35-7.24 (m, 5H),4.81 (brs, 1H), 4.08-4.03 (m, 1H), 3.38-3.21 (m, 2H), 1.44 (s, 9H).LC-MS: [M+H]⁺ 237.

Example 52

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl}-pyrimidin-2-yl]-1-phenyl-ethane-1,2-diamine;hydrochloride

Step A

(2-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (120 mg, 0.32 mmol) and(2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51supra) (305 mg, 1.29 mmol) was heated at 140° C. with stirring for 2hours. The oil was purified by chromatography (silica gel, 10 g, 200-300mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to affordcrude(2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester (Yield 44 mg).

LC-MS: [M+H]⁺ 530.

Step B

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride

To a solution of crude(2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester (44 mg, 0.083 mmol) in ethanol (3 mL) was addedconcentrated hydrochloric acid (3 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN1-{4-[4-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride (Yield 41 mg, 100%).

-   ¹H NMR (300 MHz, D₂O): δ 8.49 (s, 1H), 8.31 (s, 1H), 8.15 (d, 1H,    J=6.3 Hz), 7.47-7.23 (m, 7H), 5.45 (brs, 1H), 4.96-4.94 (m, 2H),    3.61-3.46 (m, 6H), 3.26-3.22 (m, 2H), 2.86 (s, 3H).

LC-MS: [M+H]⁺ 430.

Example 53 (3-Amino-3-phenyl-propyl)-carbamic acid tert-butyl ester

(3-Amino-3-phenyl-propyl)-carbamic acid tert-butyl ester was preparedaccording to the literature procedure of Seefeld, M. A.; Rouse, M. B.;Heerding, D. A.; Peace, S.; Yamashita, D. S.; McNulty, K. C. WO2008/098104, Aug. 14, 2008.

Step A

3-Amino-1-phenyl-propan-1-ol

To a stirred suspension of LAH (20 g, 517 mmol) in dry THF (500 mL) wasadded a solution of 3-oxo-3-phenylpropanenitrile (30 g, 207 mmol) in dryTHF (300 mL) drop-wise at 0° C. under nitrogen atmosphere. The mixturewas warmed to 25° C. and then heated at 70° C. for 2 hours. Aftercooling to 0° C., a saturated solution of sodium hydroxide was addeddrop-wise and extracted with dichloromethane (200 mL). The organicsolution was dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by column chromatography(methanol:dichloromethane, 1:10) to afford crude3-amino-1-phenyl-propan-1-ol. (Yield 30 g). LC-MS: [M+H]⁺ 152.

Step B

(3-Hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester

Et₃N (1.36 g, 14 mmol) was added to a solution of3-amino-1-phenyl-propan-1-ol (1.7 g, 11.3 mmol) in THF (20 mL) understirring. Boc₂O (3.0 g, 13.7 mmol) in THF (20 mL) was added dropwise tothe solution at 0° C. Then the resulting mixture was warmed to roomtemperature and stirred for an additional 2 hours. The mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate, 3:1) togive (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield1.7 g, 60%). LC-MS: [M+23]⁺ 274.

Step C

[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acidtert-butyl ester

To a solution of (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butylester (10.4 g, 41.4 mmol), phthalimide (5.2 g, 36.6 mmol), and PPh₃(14.6 g, 55.5 mmol) in THF (204 mL) was added dropwise DEAD (8.9 mL, 55mmol) with stirring at 0° C. Then the resulting mixture was warmed toroom temperature for an additional 2 hours. The mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate, 3:1) togive [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamicacid tert-butyl ester. (Yield 10.5 g, 66.8%). ¹H NMR (300 MHz, CDCl₃): δ7.81-7.75 (m, 2H), 7.69-7.64 (m, 2H), 7.53-7.50 (m, 2H), 7.34-7.23 (m,3H), 5.44-5.38 (m, 1H), 4.74 (brs, 1H), 3.29-3.07 (m, 2H), 2.83-2.75 (m,1H), 2.51-2.42 (m, 1H), 1.42 (s, 9H). LC-MS: [M-Boc+H]⁺ 281.

Step D

(3-Amino-3-phenyl-propyl)-carbamic acid tert-butyl ester

Hydrazine hydrate (85%, 5.1 mL, 74 mmol) was added to a solution of[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acidtert-butyl ester (2.8 g, 7.4 mmol) in THF (25 mL) and MeOH (25 mL). Theresulting mixture was heated to 65° C. for 6 hours. Then the precipitatewas filtered, and the filtrate was concentrated under reduced pressureto give crude product which was purified by column chromatography onsilica gel (dichloromethane:MeOH, 100:1, 1% NH₃ H₂O) to give(3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester as an off-whitesolid. (Yield 1.7 g, 92%). ¹H NMR (300 MHz, CDCl₃): δ 7.31-7.18 (m, 5H),6.82 (brs, 1H), 3.78-3.74 (m, 1H), 2.92 (brs, 2H), 1.82 (s, 2H),1.63-1.61 (m, 2H), 1.37 (s, 9H). LC-MS: [M+H]⁺ 251.

Example 54N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride

Step A

(3-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (120 mg, 0.32 mmol) and compound(3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example53 supra) (322 mg, 1.29 mmol) was heated at 140° C. with stirring for 2hours. The oil was purified by chromatography (silica gel, 10 g, 200-300mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to affordcrude(3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester. (Yield 51 mg).

LC-MS: [M+H]⁺ 544.

Step B

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride

To a solution of crude(3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester (51 mg, 0.094 mmol) in ethanol (3 mL) was addedconcentrated hydrochloric acid (3 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride. (Yield 59 mg, 100%).

¹H NMR (300 MHz, D₂O): δ 8.31 (brs, 1H), 8.29 (s, 1H), 8.09 (brs, 1H),7.45-7.16 (m, 6H), 5.15 (brs, 1H), 4.99-4.94 (m, 2H), 3.62-3.26 (m, 4H),3.26-3.02 (m, 4H), 2.87 (s, 3H), 2.28-2.21 (m, 2H). LC-MS: [M+H]⁺ 444.

Example 55

N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride

Step A

(2-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester

A mixture of3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 39 supra) (0.56 g, 1.5 mmol),(2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51supra) (0.425 g, 1.8 mmol), Pd₂(dba)₃ (90 mg), Davephos (120 mg), K₂CO₃(0.25 g, 1.8 mmol) in dioxane (40 mL) in a sealed tube was bubbled withN₂ for several minutes and then heated under N₂ at 130° C. overnight.The mixture was then cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure. The residue was firstpurified by chromatography (CH₂Cl₂:CH₃OH, 100:1), then bypreparative-HPLC to give(2-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester. (Yield 30 mg, 3.8%). LC-MS: [M+H]⁺ 529.

Step B

N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride

The mixture of(2-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-2-phenyl-ethyl)-carbamicacid tert-butyl ester (30 mg, 0.06 mmol) and concentrated HCl (3 mL) inethanol (3 mL) was stirred at room temperature for 15 hours. Thereaction mixture was then concentrated under reduced pressure to giveN1-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride. (Yield 40 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.54 (brs, 1H),8.13 (s, 1H), 7.64-7.46 (m, 3H), 7.31-7.10 (m, 5H), 6.92 (d, 1H, J=8.1Hz), 5.44 (brs, 3H), 3.93 (brs, 2H), 3.72-3.69 (m, 2H), 3.52-3.34 (m,4H), 2.92 (s, 3H). LC-MS: [M+H]⁺ 429.

Example 56Benzyl-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine

A mixture of3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 39 supra) (0.187 g, 0.5 mmol), benzylamine (0.075 g, 0.7mmol), Pd₂(dba)₃ (30 mg), Davephos (40 mg), NaOtBu (70 mg, 0.73 mmol) indioxane (20 mL) was bubbled with N₂ for several minutes and then heatedunder N₂ at reflux overnight. The solution was then cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure. The residue was purified firstly by chromatography(CH₂Cl₂:CH₃OH, 100:1), then by preparative-HPLC to givebenzyl-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine.(Yield 70 mg, 35%). ¹HNMR (300 MHz, CDCl₃): δ 8.70 (d, 1H, J=4.5 Hz),7.88 (s, 1H), 7.51-7.24 (m, 7H), 7.02 (d, 1H, J=7.2 Hz), 6.37 (d, 1H,J=8.1 Hz), 5.03-5.02 (m, 1H), 4.62 (d, 2H, J=3.9 Hz), 4.24 (brs, 4H),2.61-2.58 (m, 4H), 2.36 (s, 3H). LC-MS: [M+H]⁺ 400.

Example 57Benzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) and benzylamine (51.7 mg,0.482 mmol) was heated at 140° C. with stirring for 2 hours. Theresulting oil was purified by chromatography (silica gel, 10 g, 200˜300mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford thecrude product which was purified by prep-HPLC and concentrated to affordbenzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine(Yield 25 mg, 15.5%). ¹H NMR (300 MHz, CDCl₃): δ 8.71 (brs, 1H), 8.31(d, 1H, J=4.8 Hz), 8.04 (s, 1H), 7.42-7.28 (m, 5H), 6.94 (d, 1H, J=5.4Hz), 5.68 (brs, 1H), 4.71 (d, 2H, J=5.7 Hz), 4.24 (brs, 4H), 2.60-2.57(m, 4 H), 2.36 (s, 3H). LC-MS: [M+H]⁺ 401.

Example 58(2-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) and 2-chlorobenzylamine(228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours.The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh,eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crudeproduct (90 mg). The crude product was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford(2-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride. (Yield 25 mg, 14.3%). ¹H NMR (300 MHz, CD₃OD): δ 8.62 (s,1H), 8.58 (s, 1H), 8.25 (s, 1H), 7.52-7.38 (m, 4H), 7.23 (brs, 2H),5.49-5.45 (m, 2H), 4.87 (brs, 2H), 3.56 (brs, 4H), 3.24 (brs, 2H), 2.87(s, 3H). LC-MS: [M+H]⁺ 435.

Example 59(4-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) and 4-chlorobenzylamine(228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours.The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh,eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crudeproduct (100 mg). The crude product was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford(4-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride. (Yield 38 mg, 21.8%). ¹H NMR (300 MHz, CDCl₃): δ 8.68 (s,1H), 8.28 (s, 1H), 7.53 (d, 1H, J=6.9 Hz), 7.38-7.29 (m, 6H), 5.48-5.43(m, 2H), 4.76 (brs, 2H), 3.68-3.61 (m, 4H), 3.34-3.27 (m, 4H), 2.89 (s,3H). LC-MS: [M+H]⁺ 435.

Example 60N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride

Step A

(3-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester

A mixture of3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 39 supra) (0.56 g, 1.5 mmol),(3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example53 supra) (0.45 g, 1.8 mmol), Pd₂(dba)₃ (90 mg), Davephos (120 mg),K₂CO₃ (0.25 g, 1.8 mmol) in dioxane (60 mL) in a sealed tube was bubbledwith N₂ for several minutes and then heated under N₂ at 130° C. for 15hours. The solution was then cooled to room temperature and filtered.The filtrate was concentrated under reduced pressure. The residue waspurified first by chromatography (CH₂Cl₂:CH₃OH, 100:1) then bypreparative-HPLC to give(3-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester. (Yield 44 mg, 5.4%). LC-MS: [M+H]⁺ 543.

Step B

N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride

The solution of(3-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamicacid tert-butyl ester (44 mg, 0.08 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature for 15 hours.The reaction mixture was then concentrated under reduced pressure. Theresidue was suspended in CH₂Cl₂ and concentrated under reduced pressureto giveN1-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride. (Yield 25 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.39 (s, 1H),8.15 (s, 1H), 7.61 (t, 1H, J=5.7 Hz), 7.40-7.48 (m, 7H), 6.78 (brs, 1H),5.39 (brs, 1H), 5.01 (brs, 1H), 3.81-3.66 (m, 4H), 3.37 (brs, 2H),3.12-2.91 (m, 7H), 2.16-2.14 (m, 2H). LC-MS: [M+H]⁺ 443.

Example 61{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (120 mg, 0.32 mmol) and thiophen-3-ylmethanamine(145 mg, 1.28 mmol) was heated at 140° C. with stirring for 2 hours. Theoil was purified by chromatography (silica gel, 10 g, 200-300 mesh,eluting with dichloromethane:methanol, 30:1 to 10:1) to afford{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine(Yield 69 mg, 52.8%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.41 (s, 1H), 8.35(d, 1H, J=5.4 Hz), 7.94 (t, 1H, J=5.7 Hz), 7.51-7.34 (m, 3H), 7.20-7.12(m, 2H), 4.56 (d, 2H, J=5.7 Hz), 4.17 (brs, 4H), 2.52-2.44 (m, 4H), 2.23(s, 3H). LC-MS: [M+H]⁺ 407.

Example 62 [3-Amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butylester

[3-Amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester wasprepared in an analogous process according to the literature procedureof Seefeld, M. A.; Rouse, M. B.; Heerding, D. A.; Peace, S.; Yamashita,D. S.; McNulty, K. C. WO 2008/098104, Aug. 14, 2008.

Step A

3-Amino-1-(3-chloro-phenyl)-propan-1-ol

To a stirred suspension of LAH (16 g, 90 mmol) in dry THF (200 mL) wasadded a solution of 3-(3-chlorophenyl)-3-oxopropanenitrile (10.4 g, 270mmol) in dry THF (200 mL) dropwise at 0° C. under nitrogen atmosphere.The mixture was warmed to 25° C. and then heated at 60° C. for 3 hours.After cooling to 0° C., a saturated solution of sodium hydroxide wasadded dropwise and extracted with ethyl acetate (200 mL). The solutionwas dried over anhydrous sodium sulfate and concentrated to dryness. Thecrude 3-amino-1-(3-chloro-phenyl)-propan-1-ol obtained was used in thenext step without further purification. (Yield 14.5 g). LC-MS: [M+H]⁺186.

Step B

[3-(3-Chloro-phenyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester

To a stirred solution of crude 3-amino-1-(3-chloro-phenyl)-propan-1-ol(29 g, 156 mmol) in THF (300 mL) was added Boc₂O (40.5 g, 187 mmol).After 0.5 hour, the mixture was concentrated to dryness. The residue waspurified by column chromatography (ethyl acetate:petroleum ether, 1:20)to afford [3-(3-chloro-phenyl)-3-hydroxy-propyl]-carbamic acidtert-butyl ester. (Yield 23 g, 52%). LC-MS: [M+Na]⁺ 308.

Step C

[3-(3-Chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester

To a stirred solution of [3-(3-chloro-phenyl)-3-hydroxy-propyl]carbamicacid tert-butyl ester (12 g, 42 mmol), phthalimide (6.2 g, 42 mmol), andPPh₃ (14.3 g, 55 mmol) in THF (150 mL) was added DEAD (9.0 mL, 55 mmol)dropwise at about 5° C. After 1 hour, the mixture was concentrated todryness. The residue was purified by column chromatography (ethylacetate:petroleum ether, 1:8) to afford[3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamicacid tert-butyl ester. (Yield 15.65 g, 90%). LC-MS: [M+H]⁺ 415.

Step D

[3-Amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester

To a stirred solution of[3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamicacid tert-butyl ester (0.15 g, 0.36 mmol) in THF (2 mL) and methanol (2mL) was added hydrazine hydrate (0.18 g, 3.6 mmol). The mixture washeated to 55° C. for 2 hours. Then the reaction mixture was concentratedand extracted with ethyl acetate (10 mL). The organic mixture was washedwith water (3×1 mL), brine (1 mL), dried over anhydrous sodium sulfateand concentrated to dryness. The residue was purified by columnchromatography (methanol:dichloromethane, 1:100) to afford[3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester.(Yield 0.061 g, 60%). LC-MS: [M+H]⁺ 285.

Example 631-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine;hydrochloride

Step A

(3-(3-Chloro-phenyl)-3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-propyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (100 mg, 0.27 mmol) and[3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester(from Example 62 supra) (307 mg, 1.08 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to20:1) to afford crude(3-(3-chloro-phenyl)-3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-propyl)-carbamicacid tert-butyl ester. (Yield 123 mg). LC-MS: [M+H]⁺ 578.

Step B

1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine;hydrochloride

To a solution of crude(3-(3-chloro-phenyl)-3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-propyl)-carbamicacid tert-butyl ester (120 mg, 0.21 mmol) in ethanol (3 mL) was addedconcentrated hydrochloric acid (3 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford1-(3-chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine;hydrochloride. (Yield 70 mg, 48.3%). ¹H NMR (300 MHz, D₂O): δ 8.28 (brs,1H), 8.21 (s, 1H), 8.05 (brs, 1H), 7.44 (s, 1H), 7.36-7.12 (m, 5H),5.08-4.88 (m, 3H), 3.56-3.38 (m, 4H), 3.20-2.95 (m, 4H), 2.91 (s, 3H),2.25-2.10 (m, 2H). LC-MS: [M+H]⁺ 478.

Example 64{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine;hydrochloride

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) andthiophen-2-ylmethanamine (182 mg, 1.608 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to10:1) to afford the crude product (115 mg). The crude product waspurified by prep-HPLC. Several drops of concentrated HCl were added tothe fractions with product. After sonicating for several minutes,solution was concentrated under reduced pressure to afford{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine;hydrochloride. (Yield 34 mg, 21.2%). ¹H NMR (300 MHz, CD₃OD): δ 9.02(brs, 1H), 8.84 (s, 1H), 8.39 (d, 1H, J=6.3 Hz), 7.69-7.63 (m, 2H), 7.40(brs, 1H), 7.23 (s, 1H), 7.06-7.03 (m, 1H), 5.62-5.51 (m, 2H), 5.06-4.99(m, 2H), 3.88-3.75 (m, 4H), 3.48-3.37 (m, 2H), 3.00 (s, 3H). LC-MS:[M+H]⁺ 407.

Example 65(2-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;hydrochloride

A mixture of3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 39 supra) (0.187 g, 0.5 mmol), 2-chloro-benzylamine (71mg, 0.5 mmol), Pd₂(dba)₃ (30 mg), Davephos (40 mg), NaOtBu (70 mg, 0.73mmol) and dioxane (20 mL) in a sealed tube was bubbled with N₂ forseveral minutes and then heated under N₂ at 100° C. for 15 hours. Thesolution was then cooled to room temperature and filtered. The filtratewas concentrated under reduced pressure. The obtained crude product waspurified by preparative-HPLC. The obtained product was dissolved inethanol and then concentrated HCl (1 mL) was added and stirred for 1 h.The mixture was concentrated under reduced pressure. The resulting solidwas suspended in dichloromethane and concentrated to give(2-chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl}-pyridin-2-yl]-amine;hydrochloride. (Yield 47 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.39 (d, 1H,J=5.4 Hz), 8.17 (s, 1H), 7.73 (t, 1H, J=7.8 Hz), 7.40-7.36 (m, 2H),7.22-7.09 (m, 4H), 6.87 (d, 1H, J=8.4 Hz), 5.43 (brs, 2H), 4.64 (s, 2H),3.86-3.66 (m, 4H), 3.41-3.37 (m, 2H), 2.91 (s, 3H). LC-MS: [M+H]⁺ 435.

Example 66(3-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) and 3-chlorobenzylamine(228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours.The resulting oil was purified by chromatography (silica gel, 10 g,200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) toafford the crude product (120 mg). Then the crude product was purifiedby prep-HPLC. Several drops concentrated HCl were added to the fractionswith product. After sonicating for several minutes, solution wasconcentrated under reduced pressure to afford(3-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 45 mg,25.8%).

¹H NMR (300 MHz, CD₃OD): δ 8.77 (s, 2H), 8.36 (brs, 1H), 7.64-7.36 (m,6H), 5.59-5.55 (m, 3H), 4.98-4.96 (m, 1H), 3.69-3.63 (m, 4H), 3.41 (brs,2H), 3.00 (s, 3H). LC-MS: [M+H]⁺ 436.

Example 67N-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

The mixture of{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 48 supra) (100 mg, 0.212 mmol) and(3-chlorobenzylamine (120.3 mg, 0.849 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to30:1) to afford crude(4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]⁺ 549.

Step B

N-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

To a solution of crude(4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (110 mg, 0.205 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 58 mg, 60.9%).

¹H NMR (300 MHz, CD₃OD): δ 8.75 (s, 1H), 8.45 (brs, 1H), 7.66-7.53 (m,2H), 7.42-7.26 (m, 5H), 4.92 (brs, 2H), 4.07 (brs, 1H), 3.25 (brs, 1H),2.23 (brs, 4H), 1.78-1.75 (m, 4H). LC-MS: [M+H]⁺ 450.

Example 68N-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride

Step A

{4-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester

The mixture of{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 48 supra) (130 mg, 0.276 mmol) andbenzylamine (118.2 mg, 1.104 mmol) was heated at 140° C. with stirringfor 2 hours. The oil was purified by chromatography (silica gel, 10 g,200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) toafford crude{4-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]⁺ 515.

Step B

N-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride

To a solution of crude{4-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (400 mg, 0.182 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride. (Yield 33 mg, 28.9%). ¹H NMR (300 MHz, CD₃OD): δ 8.73 (s,1H), 8.45 (brs, 2H), 7.61-7.32 (m, 7H), 4.91 (brs, 2H), 4.11 (brs, 1H),3.25 (brs, 1H), 2.23 (brs, 4H), 1.77-1.75 (m, 4H). LC-MS: [M+H]⁺ 415.

Example 69 (3-Amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butylester

(3-Amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester wasprepared in an analogous process according to the literature procedureof Seefeld, M. A.; Rouse, M. B.; Heerding, D. A.; Peace, S.; Yamashita,D. S.; McNulty, K. C. WO 2008/098104, Aug. 14, 2008.

Step A

3-Amino-1-thiophen-3-yl-propan-1-ol

To a stirred suspension of LAH (1.45 g, 38.1 mmol) in dry THF (120 mL)was added a solution of 3-oxo-3-(thiophen-3-yl)propanenitrile (4.8 g,31.8 mmol) in dry THF (40 mL) dropwise at 0° C. under nitrogenatmosphere. The mixture was warmed to 25° C. and then heated at 65° C.for 6 hours. After cooling to 0° C., a saturated solution of sodiumhydroxide (2 mL) was added dropwise and the mixture was filtered. Thefiltrate was concentrated to dryness to give crude3-amino-1-thiophen-3-yl-propan-1-ol which was used in next step withoutfurther purification. ¹H NMR (300 MHz, CDCl₃): δ 7.29-7.26 (m, 2H), 7.05(dd, 1H, J₁=4.8 Hz, J₂=1.2 Hz), 5.04 (dd, 1H, J₁=8.1 Hz, J₂=3.0 Hz),3.10-3.05 (m, 2H), 1.82-1.77 (m, 2H).

Step B

(3-Hydroxy-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester

To a stirred solution of crude 3-amino-1-thiophen-3-yl-propan-1-ol (23g) in THF (100 mL) was added Boc₂O (31.6 g, 146.3 mmol). The mixture wasstirred at room temperature for 1 hour and then concentrated to dryness.The residue was purified by column chromatography (ethylacetate:petroleum ether, 1:10) to afford(3-hydroxy-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester.(Yield 21.5 g, 51% for two steps). ¹H NMR (300 MHz, CDCl₃): δ 8.08-8.06(m, 1H), 7.55-7.53 (m, 1H), 7.34-7.30 (m, 1H), 5.10 (s, 1H), 3.52-3.48(m, 2H), 3.13-3.09 (m, 2H), 1.42 (s, 9H). LC-MS: [M+Na]⁺ 280.

Step C

3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-thiophen-3-yl-propyl]-carbamicacid tert-butyl ester

To a stirred solution of (3-hydroxy-3-thiophen-3-yl-propyl)-carbamicacid tert-butyl ester (21.5 g, 83.6 mmol), phthalimide (12.3 g, 83.6mmol), and PPh₃ (28.5 g, 108.6 mmol) in THF (400 mL) was added DEAD(17.6 mL, 108.6 mmol) dropwise at 25° C. The mixture was stirred at roomtemperature for 14 hours, then concentrated. The residue was purified bycolumn chromatography (ethyl acetate:petroleum ether, 1:6) to afford3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-thiophen-3-yl-propyl]-carbamicacid tert-butyl ester. (Yield 12 g, 38%).

¹H NMR (300 MHz, CDCl₃): δ 7.82-7.77 (m, 2H), 7.72-7.68 (m, 2H), 7.36(d, 1H, J=1.8 Hz), 7.26-7.18 (m, 2H), 5.50 (dd, 1H, J₁=9.6 Hz, J₂=6 Hz),4.65 (brs, 1H), 3.24-3.07 (m, 2H), 2.72-2.67 (m, 1H), 2.47-2.40 (m, 1H),1.40 (s, 9H). LC-MS: [M+H−Boc]⁺ 287.

Step D

(3-Amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester

To a stirred solution of3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-thiophen-3-yl-propyl]-carbamicacid tert-butyl ester (12 g, 31.1 mmol) in methanol (150 mL) was addedhydrazine hydrate (18 mL, 85% aqueous). The mixture was heated at refluxfor 14 hours. After cooling to room temperature, the reaction mixturewas filtered. The filtrate was concentrated and the residue was purifiedby column chromatography (methanol:dichloromethane, 1:50 to 1:20, 0.1%NH₃ H₂O) to afford (3-amino-3-thiophen-3-yl-propyl)-carbamic acidtert-butyl ester. (Yield 7.6 g, 95%). ¹H NMR (300 MHz, CDCl₃): δ 7.49(s, 1H), 7.25-7.08 (m, 2H), 6.82 (brs, 1H), 3.85 (t, 1H, J=6.0 Hz),3.18-2.95 (m, 4H), 1.75-1.62 (m, 2H), 1.37 (s, 9H). LC-MS: [M+H]⁺ 257.

Example 70N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine;hydrochloride

Step A

(3-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (150 mg, 0.402 mmol) and(3-amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester (fromExample 69 supra) (412 mg, 1.608 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to20:1) to afford crude(3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamicacid tert-butyl ester. (Yield 400 mg).

Step B

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine;hydrochloride

To a solution of crude(3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamicacid tert-butyl ester (400 mg, 0.182 mmol) in ethanol (3 mL) was addedconcentrated hydrochloric acid (3 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine;hydrochloride. (Yield 27 mg, 14.9%). ¹H NMR (300 MHz, CD₃OD): δ 8.76 (s,2H), 8.41 (brs, 1H), 7.68-7.52 (m, 4H), 7.32 (d, 1H, J=5.1 Hz), 5.55(brs, 1H), 4.85 (brs, 2H), 3.75-3.72 (m, 4H), 3.40(brs, 2H), 3.18-3.15(m, 2H), 3.00 (s, 3H), 2.44 (brs, 2H). LC-MS: [M+H]⁺ 450.

Example 71(4-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;hydrochloride

A mixture of3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 39 supra) (0.373 g, 1.0 mmol), 4-chloro-benzylamine (0.14g, 1.0 mmol), Pd₂(dba)₃ (60 mg), Davephos (80 mg), NaOtBu (140 mg, 1.46mmol) suspended in dioxane (25 mL). The solution was bubbled with N₂ forseveral minutes and then heated under N₂ at 100° C. for 15 hours. Thesolution was then cooled to room temperature and filtered. The filtratewas concentrated under reduced pressure. The obtained crude product waspurified by preparative-HPLC to give(4-chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;hydrochloride. (Yield 31 mg, 7.1%).

¹H NMR (300 MHz, CD₃OD): δ 8.54 (s, 1H), 8.23 (s, 1H), 7.76 (t, 1H,J=8.1 Hz), 7.42-7.35 (m, 4H), 7.25-7.20 (m, 2H), 6.88-6.85 (m, 1H),5.50-5.46 (m, 2H), 4.65 (s, 2H), 3.78-3.74 (m, 4H), 3.42 (brs, 2H), 3.01(s, 3H). LC-MS: [M+H]⁺ 434.

Example 72[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;hydrochloride

The mixture of[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 50 supra) (120 mg, 0.30 mmol) and benzylamine (128 mg,1.19 mmol) was heated at 140° C. with stirring for 2 hours. The oil waspurified by chromatography (silica gel, 10 g, 200-300 mesh, eluting withdichloromethane:methanol, 30:1 to 10:1) to afford the crude product (100mg). The crude product was purified by prep-HPLC. Several drops ofconcentrated HCl were added to the fractions with product. Aftersonicating for several minutes, solution was concentrated under reducedpressure to afford[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;hydrochloride. (Yield 25 mg, 19.5%). ¹H NMR (300 MHz, CD₃OD): δ 8.77 (s,1H), 8.57-8.38 (m, 2H), 7.62 (d, 1H, J=6.6 Hz), 7.48-7.34 (m, 6H), 4.82(brs, 2H), 4.21 (brs, 2H), 3.99 (brs, 4H), 3.63-3.47 (m, 6H). LC-MS:[M+H]⁺ 431.

Example 73N-[3-(6-Benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride

Step A

{4-[3-(6-Benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol),benzylamine (0.214 g, 2.0 mmol), Pd₂(dba)₃ (60 mg), Davephos (80 mg),NaOtBu (140 mg, 1.46 mmol) in dioxane (25 mL) in a sealed tube wasbubbled with N₂ for several minutes and then heated under N₂ at 110° C.for 15 hours. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theobtained crude product was purified by preparative-HPLC to give{4-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]⁺ 514.

Step B

N-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride

The mixture of{4-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (80 mg, 0.156 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature for 15 hours.The reaction mixture was then concentrated under reduced pressure. Theobtained crude product was purified by preparative-HPLC to giveN-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride. (Yield 50 mg).

¹H NMR (300 MHz, CD₃OD): δ 8.16 (s, 1H), 8.06 (d, 1H, J=5.7 Hz), 7.93(t, 1H, J=8.4 Hz), 7.45-7.17 (m, 7H), 7.09 (d, 1H, J=9.0 Hz), 4.70 (s,2H), 4.04 (brs, 1H), 3.23 (brs, 1H), 2.22-2.15 (m, 4H), 1.80-1.75 (m,4H). LC-MS: [M+H]⁺ 414.

Example 74 (2-Amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butylester

(2-Amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester wasprepared in an analogous process according to the literature procedureof Seefeld, M. A.; Rouse, M. B.; Heerding, D. A.; Peace, S.; Yamashita,D. S.; McNulty, K. C. WO 2008/098104, Aug. 14, 2008.

Step A

Hydroxy-thiophen-3-yl-acetonitrile

To a stirred suspension of KCN (18.6 g, 286 mmol) in methanol (100 mL)was added thiophene-3-carbaldehyde (20 mL, 178 mmol) at 0° C. undernitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0°C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 20hours. NaHCO₃ (15 g) was added. The mixture was concentrated andextracted with ethyl acetate (200 mL). The organic mixture was washedwith water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfateand concentrated to dryness. The residue was purified by columnchromatography (ethyl acetate:petroleum ether, 1:10) to affordhydroxy-thiophen-3-yl-acetonitrile. (Yield 15 g, 60%). LC-MS: [M+Na]⁺162.

Step B

2-Amino-1-thiophen-3-yl-ethanol

To a stirred suspension of LAH (8.7 g, 225 mmol) in dry THF (300 mL) wasadded a solution of hydroxy-thiophen-3-yl-acetonitrile (12.5 mL, 90mmol) in dry THF (50 mL) dropwise at 0° C. under nitrogen atmosphere.Then the mixture was warmed to 25° C. and stirred overnight. Aftercooling to 10° C., H₂O (8.7 mL) was added to the solution, followed byNaOH solution (8.7 mL, 15%), then H₂O (26 mL). The reaction mixture wasfiltered and the filtrate was concentrated to dryness to afford crude2-amino-1-thiophen-3-yl-ethanol. (Yield 12.9 g, crude). LC-MS: [M+H]⁺144.

Step C

(2-Hydroxy-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester

To a stirred solution of crude 2-amino-1-thiophen-3-yl-ethanol (12.9 g,crude) in THF (150 mL) was added Boc₂O (21.6 g, 99 mmol). After stirringfor 1 hour, the mixture was concentrated to dryness which was purifiedby column chromatography (ethyl acetate:petroleum ether, 1:5) to afford(2-hydroxy-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester. (Yield15.3 g, 70%). LC-MS: [M+Na]⁺ 266.

Step D

[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-thiophen-3-yl-ethyl]-carbamicacid tert-butyl ester

To a stirred solution of (2-hydroxy-2-thiophen-3-yl-ethyl)-carbamic acidtert-butyl ester (15.3 g, 63 mmol), pathalimide (9.5 g, 63 mmol), PPh₃(21.4 g, 82 mmol) in THF (400 mL) was added DEAD (12.6 mL, 82 mmol)dropwise at 25° C. After 20 hours, the mixture was concentrated todryness. The residue was purified by column chromatography (ethylacetate:petroleum ether, 1:6) to afford crude[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-thiophen-3-yl-ethyl]-carbamicacid tert-butyl ester. (Yield 23 g).

LC-MS: [M+Na]⁺ 395.

Step E

(2-Amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester

To a stirred solution of[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-thiophen-3-yl-ethyl]-carbamicacid tert-butyl ester (23 g, crude) in THF (100 mL) and methanol (100mL) was added hydrazine hydrate (63 g, 1.26 mol). The mixture was heatedto 60° C. for 2 hours and then cooled to 20° C. The reaction mixture wasfiltered and the filtration was concentrated to dryness. The residue waspurified by column chromatography (methanol:dichloromethane, 1:50) toafford (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester.(Yield 8.6 g, 57% for the two steps). LC-MS: [M+H]⁺ 243.

Example 75N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine; hydrochloride

Step A

(2-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (200 mg, 0.536 mmol) and(2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (fromExample 74 supra) (520 mg, 2.14 mmol) was heated at 140° C., withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to4:1) to afford crude(2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamicacid tert-butyl ester. (yield 150 mg). LC-MS: [M+H]⁺ 536.

Step B

N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine; hydrochloride

To a solution of crude(2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamicacid tert-butyl ester (150 mg, 0.280 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine;hydrochloride. (Yield 13 mg, 5.57%). ¹H NMR (300 MHz, CD₃OD): δ 8.81(brs, 1H), 8.63 (s, 1H), 8.29 (d, 1H, J=6.0 Hz), 7.61-7.52 (m, 3H),7.46-7.43 (m, 1H), 7.23 (d, 1H, J=5.1 Hz), 5.72 (brs, 1H), 5.47-5.43 (m,2H), 3.63-3.60 (m, 4H), 3.50-3.48 (m, 2H), 3.29-3.26 (m, 2H), 2.89 (s,3H). LC-MS: [M+H]⁺ 436.

Example 76N-{3-[2-(3-Amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[2-(3-tert-Butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

The mixture of{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) andcompound (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (fromExample 53 supra) (361 mg, 1.44 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to30:1) to afford crude(4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 110 mg).

LC-MS: [M+H]⁺ 658.

Step B

N-{3-[2-(3-Amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

To a solution of crude(4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (110 mg, 0.17 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN-{3-[2-(3-amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 27 mg, 16.4%). ¹H NMR (300 MHz, CD₃OD): δ 8.67 (s,2H), 8.43 (brs, 1H), 7.57-7.55(m, 3H), 7.44-7.31(m, 4H), 5.38 (s, 1H),4.08 (brs, 1H), 3.21-3.16(m, 3H), 2.42-2.25(m, 6H), 1.75-1.73(m, 4H).

LC-MS: [M+H]⁺ 458.

Example 77N-{3-[2-(2-Amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[2-(2-tert-Butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

The mixture of{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) and(2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51supra) (341 mg, 1.44 mmol) was heated at 140° C. with stirring for 2hours. The oil was purified by chromatography (silica gel, 10 g, 200-300mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to affordcrude(4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 100 mg). LC-MS: [M+H]⁺ 644.

Step B

N-{3-[2-(2-Amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

To a solution of crude(4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (100 mg, 0.16 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN-{3-[2-(2-amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 26 mg, 16.3%). ¹H NMR (300 MHz, CD₃OD): δ 8.68 (s,2H), 8.46 (brs, 1H), 7.63-7.61(m, 3H), 7.46-7.32(m, 4H), 5.78 (s, 1H),4.05 (brs, 1H), 3.61-3.48(m, 2H), 3.23 (brs, 1H), 2.22 (brs, 4H),1.76-1.71(m, 4H).

LC-MS: [M+H]⁺ 444.

Example 78 [2-Amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butylester

[2-Amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester wasprepared in an analogous process according to the literature procedureof Seefeld, M. A.; Rouse, M. B.; Heerding, D. A.; Peace, S.; Yamashita,D. S.; McNulty, K. C. WO 2008/098104, Aug. 14, 2008.

Step A

(3-Chloro-phenyl)-hydroxy-acetonitrile

To a stirred suspension of KCN (5.04 g, 78 mmol) in methanol (20 mL) wasadded 3-chlorobenzaldehyde (7.0 g, 50 mmol) at 0° C. under nitrogenatmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After30 minutes, the mixture was warmed to 15° C. and stirred for 5 hours.Then the reaction mixture was concentrated to dryness and extracted withethyl acetate (200 mL). The organic solution was washed with water (3×25mL), brine (25 mL), dried over anhydrous sodium sulfate and concentratedto dryness. The resulting residue was purified by column chromatography(ethyl acetate:petroleum ether, 1:15) to afford(3-chloro-phenyl)-hydroxy-acetonitrile. (Yield 8.2 g, 97%). LC-MS:[M+Na]⁺ 190.

Step B

2-Amino-1-(3-chloro-phenyl)-ethanol

To a stirred suspension of LAH (2.36 g, 59 mmol) in dry THF (70 mL) wasadded a solution of (3-chloro-phenyl)-hydroxy-acetonitrile (4.0 g, 24mmol) in dry THF (55 mL) dropwise at 0° C. under nitrogen atmosphere.The mixture was warmed to 25° C. and then heated at 60° C. for 2 hours.After cooling to 0° C., a saturated solution of sodium hydroxide wasadded dropwise and extracted with dichloromethane (200 mL). The organicsolution was dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by column chromatography(methanol:dichloromethane, 1:10) to afford2-amino-1-(3-chloro-phenyl)-ethanol. (Yield 2.86 g, 70%). LC-MS: [M+H]⁺172.

Step C

[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester

To a stirred solution of 2-amino-1-(3-chloro-phenyl)-ethanol (2.86 g,16.7 mmol) in THF (100 mL) was added Boc₂O (4.3 g, 20 mmol). After 1hour, the mixture was concentrated to dryness. The residue was purifiedby column chromatography (methanol:dichloromethane, 1:100) to afford[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester.(Yield 3.9 g, 72%). LC-MS: [M+Na]⁺ 294.

Step D

[2-(3-Chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamic acid tert-butyl ester

To a stirred solution of [2-(3-chloro-phenyl)-2-hydroxy-ethyl]carbamicacid tert-butyl ester (20 g, 73.5 mmol), phthalimide (11.1 g, 73.5 mmol)and PPh₃ (25.1 g, 95.5 mmol) in THF (500 mL) was added DEAD (11.4 mL,95.5 mmol) dropwise at −5 to 0° C. The reaction mixture was stirred atroom temperature for 3 hours. Then the mixture was concentrated todryness. The residue was purified by column chromatography (ethylacetate:petroleum ether, 1:10) to afford[2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamicacid tert-butyl ester. (Yield 20 g, 69%). LC-MS: [M+H]⁺ 401.

Step E

[2-Amino-2-(3-chloro-phenyl)-ethyl]carbamic acid tert-butyl ester

To a stirred solution of[2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethy]-carbamicacid tert-butyl ester (2.5 g, 6.2 mmol) in THF (10 mL) and methanol (10mL) was added hydrazine hydrate (3.1 g, 62 mmol). The mixture was heateda 55° C. for 1 hour. Then it was concentrated to dryness, dissolved inH₂O (5 mL) and extracted with ethyl acetate (50 mL). The organic mixturewas concentrated and purified by column chromatography(methanol:dichloromethane, 1:100) to afford[2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester.(Yield 1.325 g, 79%). LC-MS: [M+H]⁺ 271.

Example 791-(3-Chloro-phenyl)-N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine;hydrochloride

Step A

(2-(3-Chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester

The mixture of3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine(from Example 46 supra) (210 mg, 0.563 mmol) and[2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (fromExample 78 supra) (611 mg, 2.25 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to4:1) to afford crude(2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester. (Yield 150 mg). LC-MS: [M+H]⁺ 564.

Step B

1-(3-Chloro-phenyl)-N-1-{-4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine;hydrochloride

To a solution of crude(2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester (150 mg, 0.266 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford1-(3-chloro-phenyl)-N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine;hydrochloride. (Yield 28 mg, 10.7%). ¹H NMR (300 MHz, CD₃OD): δ 8.79(brs, 1H), 8.59 (s, 1H), 8.30 (d, 1H, J=6.3 Hz), 7.59-7.45 (m, 4H),7.37-7.27 (m, 2H), 5.62 (brs, 1H), 5.45 (brs, 2H), 3.64-3.60 (m, 4H),3.48-3.38 (m, 4H), 2.89 (s, 3H). LC-MS: [M+H]⁺ 465.

Example 80N-{3-[6-(2-Amino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[6-(2-tert-Butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

A sealed tube was charged with the mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (487 mg, 1.0 mmol),compound (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (fromExample 51 supra) (354 mg, 1.5 mmol), Pd₂(dba)₃(46 mg, 0.05 mmol),Davephos (78 mg, 0.2 mmol), K₂CO₃ (207 mg, 1.5 mmol) and dioxane (20mL). The mixture was bubbled with N₂ for several minutes and then heatedunder N₂ at 135° C. for 17 hours. The solution was then cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by chromatography (CH₂Cl₂:MeOH,100:1) to give crude(4-{3-[6-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 0.38 g).

Step B

N-{3-[6-(2-Amino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

To a solution of(4-{3-[6-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (0.38 g, crude) in ethanol (4 mL) was addedconcentrated HCl (8 mL). The reaction mixture was stirred at roomtemperature for 15 hour and then concentrated under reduced pressure.The residue was purified by prep-HPLC to giveN-{3-[6-(2-amino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 47 mg).

¹H NMR (300 MHz, CD₃OD): δ 8.45 (d, 1H, J=5.7 Hz), 8.13 (s, 1H), 7.65(t, 1H, J=7.2 Hz), 7.53-7.51 (m, 2H), 7.43-7.06 (m, 5H), 6.85 (d, 1H,J=8.7 Hz), 5.47-5.41 (m, 1H), 4.03 (brs, 1H), 3.43-3.23 (m, 3H), 2.20(brs, 4H), 1.73 (brs, 4H). LC-MS: [M+H]⁺ 443.

Example 81N-{3-[6-(3-Amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[6-(3-tert-Butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol),(3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example53 supra) (0.375 g, 1.5 mmol), Pd₂(dba)₃ (60 mg), Davephos (80 mg),K₂CO₃ (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube was bubbledwith N₂ for several minutes and then heated under N₂ at 130° C. for 15hours. The solution was then cooled to room temperature and filtered.The filtrate was concentrated under reduced pressure. The residue waspurified first by chromatography (CH₂Cl₂:MeOH, 100:1), then bypreparative-HPLC to give(4-{3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 250 mg). LC-MS: [M+H]⁺ 657.

Step B

N-{3-[6-(3-Amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

The mixture of(4-{3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (250 mg, 0.38 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by preparative-HPLC to giveN-{3-[6-(3-amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 18 mg).

¹H NMR (300 MHz, CD₃OD): δ 8.20 (brs, 1H), 8.13 (s, 1H), 7.74-7.70 (m,1H), 7.50-7.37 (m, 4H), 7.32-7.30 (m, 1H), 7.17-7.07 (m, 2H), 6.89 (d,1H, J=8.4 Hz), 5.13-5.10 (m, 1H), 4.05 (brs, 1H), 3.22-3.17 (m, 3H),2.26-2.24 (m, 6H), 1.73 (brs, 4H). LC-MS: [M+H]⁺ 457.

Example 82N-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol),3-chloro-benzylamine (0.283 g, 2.0 mmol), Pd₂(dba)₃ (60 mg), Davephos(80 mg), NaOtBu (200 mg, 0.2 mmol) in dioxane (25 mL) in a sealed tubewas bubbled with N₂ for several minutes and then heated under N₂ at 110°C. for 15 hours. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theobtained crude product was purified by preparative-HPLC to give(4-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 430 mg). LC-MS: [M+H]⁺ 548.

Step B

N-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride

The mixture of(4-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (430 mg, 0.78 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure. Theobtained crude product was purified by preparative-HPLC to giveN-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 100 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.16-8.13 (m,2H), 7.91 (t, 1H, J=8.1 Hz), 7.46 (s, 1H), 7.38-7.31 (m, 3H), 7.22-7.17(m, 2H), 7.04 (d, 1H, J=8.7 Hz), 4.69 (s, 2H), 4.06 (s, 1H), 3.23 (brs,1H), 2.21 (brs, 4H), 1.76-1.70 (m, 4H). LC-MS: [M+H]⁺ 448.

Example 83N-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

The mixture of{4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 48 supra) (100 mg, 0.21 mmol) and2-chlorobenzylamine (120 mg, 0.84 mmol) was heated at 140° C. withstirring for 2 hours. The oil was purified by chromatography (silicagel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to30:1) to afford crude(4-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 60 mg).

Step B

N-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

To a solution of crude(4-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (60 mg, 0.11 mmol) in ethanol (5 mL) was addedconcentrated hydrochloric acid (5 mL) slowly. The reaction mixture wasstirred at room temperature for 15 hours. The solvent was removed underreduced pressure and then the solid was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to affordN-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 23 mg, 24.2%).

¹H NMR (300 MHz, CD₃OD): δ 8.70 (s, 1H), 8.44 (brs, 2H), 7.60-7.49 (m,3H), 7.35 (brs, 2H), 7.15 (s, 1H), 4.84 (s, 2H), 4.06 (brs, 1H), 3.23(s, 1H), 2.25-2.19 (m, 4H), 1.78-1.68 (m, 4H). LC-MS: [M+H]⁺ 449.

Example 84N-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride

Step A

[4-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol),compound thiophen-3-yl-methylamine (0.113 g, 1.0 mmol), Pd₂(dba)₃ (30mg), Davephos (40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (12 mL) in asealed tube was bubbled with N₂ for several minutes and then heatedunder N₂ at 110° C. for 16 hours. The solution was then cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by chromatography (CH₂Cl₂:MeOH,100:1) to give[4-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester. (Yield 70 mg, 27%).

Step B

N-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride

The mixture of[4-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester (70 mg, 0.135 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature for 15 h. Thereaction mixture was then concentrated under reduced pressure to giveN-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride. (Yield 83 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.06 (s, 1H),7.94 (d, 1H, J=5.4 Hz), 7.87 (t, 1H, J=8.7 Hz), 7.39-7.34 (m, 2H),7.16-7.03 (m, 4H), 4.62 (s, 2H), 3.98 (brs, 1H), 3.14 (brs, 1H),2.14-2.09 (brs, 4H), 1.70-1.60 (m, 4H). LC-MS: [M+H]⁺ 420.

Example 85N-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol),2-chloro-benzylamine (0.143 g, 1.0 mmol), Pd₂(dba)₃ (30 mg), Davephos(40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (12 mL) in a sealed tubewas bubbled with N₂ for several minutes and then heated under N₂ at 110°C. overnight. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography (CH₂Cl₂:MeOH, 100:1) to give(4-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 227 mg, 83%).

Step B

N-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

The mixture of(4-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (227 mg, 0.41 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by preparative-HPLC to giveN-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 60 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.25 (d, 1H,J=5.7 Hz), 8.19 (s, 1H), 7.88 (t, 1H, J=8.7 Hz), 7.53-7.50 (m, 2H),7.35-7.22 (m, 3H), 7.10 (d, 1H, J=5.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 4.77(s, 2H), 4.05 (brs, 1H), 3.32 (brs, 1H), 2.23 (brs, 4H), 1.81-1.74 (m,4H). LC-MS: [M+H]⁺ 448.

Example 86N-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

Step A

(4-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol),4-chloro-benzylamine (0.143 g, 1.0 mmol), Pd₂(dba)₃ (30 mg), Davephos(40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (12 mL) in a sealed tubewas bubbled with N₂ for several minutes and then heated under N₂ at 110°C. for 14 hours. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography (CH₂Cl₂:MeOH, 100:1) to give(4-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester. (Yield 214 mg, 78%).

Step B

N-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride

A mixture of(4-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamicacid tert-butyl ester (214 mg, 0.39 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by preparative-HPLC to giveN-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride. (Yield 80 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.22 (d, 1H,J=5.7 Hz), 8.19 (s, 1H), 7.89 (t, 1H, J=8.7 Hz), 7.46-7.39 (m, 4H), 7.23(d, 1H, J=6.9 Hz), 7.17 (d, 1H, J=5.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 4.70(s, 2H), 4.04 (brs, 1H), 3.25 (brs, 1H), 2.23 (brs, 4H), 1.81-1.71 (m,4H). LC-MS: [M+H]⁺ 448.

Example 87N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride

Step A

[4-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester

A mixture of{4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol),thiophen-2-yl-methylamine (0.113 g, 1.0 mmol), Pd₂(dba)₃ (30 mg),Davephos (40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (15 mL) in asealed tube was bubbled with N₂ for several minutes and then heatedunder N₂ at 110° C. for 16 hour. The solution was then cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure. The residue was purified first by chromatography (CH₂Cl₂:MeOH,100:1), then by preparative-HPLC to give[4-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester. (Yield 100 mg, 38%). LC-MS: [M+H]⁺ 520.

Step B

N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride

The mixture of[4-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamicacid tert-butyl ester (100 mg, 0.193 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by prepara-HPLC to giveN-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride. (Yield 30 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.59-8.56 (m,1H), 8.38 (brs, 1H), 7.82 (d, 1H, J=9.0 Hz), 7.42-7.34 (m, 1H),7.16-7.04 (m, 2H), 6.98-6.85 (m, 2H), 6.43-6.39 (m, 1H), 4.70 (d, 2H,J=5.1 Hz), 3.89-3.85 (m, 1H), 3.23-3.07 (m, 1H), 2.20-2.05 (m, 4H),1.60-1.37 (m, 4H). LC-MS: [M+H]⁺ 420.

Example 88{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride

A mixture of[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 50 supra) (200 mg, 0.50 mmol) and 2-chlorobenzylamine (281mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oilwas purified by chromatography (silica gel, 10 g, 200-300 mesh, elutingwith dichloromethane:methanol 50:1 to 20:1) to afford the crude product(110 mg). Then the crude product was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride. (Yield 58 mg, 25.1%). ¹H NMR (300 MHz, CD₃OD): δ 8.72 (s,1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.59 (d, 1H, J=6.9 Hz), 7.46-7.28 (m,5H), 4.75 (brs, 2H), 4.17 (brs, 2H), 3.93 (brs, 4H), 3.59-3.28 (m, 5H).LC-MS: [M+H]⁺ 466.

Example 89{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride

The mixture of[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 50 supra) (200 mg, 0.50 mmol) and 3-chlorobenzylamine (281mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oilwas purified by chromatography (silica gel, 10 g, 200-300 mesh, elutingwith dichloromethane:methanol, 50:1˜20:1) to afford the crude product(125 mg). Then the crude product was purified by prep-HPLC. Severaldrops of concentrated HCl were added to the fractions with product.After sonicating for several minutes, solution was concentrated underreduced pressure to afford{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride. (Yield 60 mg, 26.0%). ¹H NMR (300 MHz, CD₃OD): δ 8.71 (s,1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.59 (d, 1H, J=6.6 Hz), 7.49-7.28 (m,5H), 4.87 (brs, 2H), 4.16 (brs, 2H), 3.93 (brs, 4H), 3.58-3.28 (m, 5H).LC-MS: [M+H]⁺ 466.

Example 901-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diaminehydrochloride

Step A

(3-(3-Chloro-phenyl)-3-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-propyl)-carbamicacid tert-butyl ester

A mixture of[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 41 supra) (0.403 g, 1.0 mmol),[3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester(from Example 62 supra) (0.427 g, 1.5 mmol), Pd₂(dba)₃ (60 mg), Davephos(80 mg), K₂CO₃ (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tubewas bubbled with N₂ for several minutes and then heated under N₂ at 130°C. overnight. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by preparative-HPLC to give(3-(3-chloro-phenyl)-3-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-propyl)-carbamicacid tert-butyl ester. (Yield 50 mg). LC-MS: 607 [M+H]⁺ 607.

Step B

1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diaminehydrochloride

The mixture of(3-(3-chloro-phenyl)-3-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-propyl)-carbamicacid tert-butyl ester (50 mg, 0.08 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure to give1-(3-chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diaminehydrochloride. (Yield 50 mg). ¹HNMR (300 MHz, CD₃OD): δ 8.51 (s, 1H),8.24 (s, 1H), 7.66-7.63 (m, 1H), 7.54 (s, 1H), 7.45-7.19 (m, 5H),6.84-6.80 (m, 1H), 5.11(brs, 1H), 4.24 (brs, 2H), 4.00 (brs, 4H),3.65-3.49 (m, 6H), 3.24-3.10 (m, 2H), 2.23 (brs, 2H). LC-MS: 508 [M+H]⁺508.

Example 911-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diaminehydrochloride

Step A

(2-(3-Chloro-phenyl)-2-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester

A mixture of[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine(from Example 41 supra) (0.403 g, 1.0 mmol),[2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (fromExample 78 supra) (0.406 g, 1.5 mmol), Pd₂(dba)₃(60 mg), Davephos (80mg), K₂CO₃ (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube wasbubbled with N₂ for several minutes and then heated under N₂ at 130° C.overnight. The solution was then cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure. Theobtained residue was purified by chromatography (CH₂Cl₂:MeOH, 50:1 to20:1) to give crude(2-(3-chloro-phenyl)-2-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester. (Yield 210 mg). LC-MS: [M+H]⁺ 593.

Step B

1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diaminehydrochloride

The mixture of crude(2-(3-chloro-phenyl)-2-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester (210 mg, 0.35 mmol) in ethanol (4 mL) andconcentrated HCl (4 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure to give1-(3-chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diaminehydrochloride. (Yield 150 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.58 (s, 1H),8.27 (s, 1H), 7.68-7.63 (m, 2H), 7.51-7.39 (m, 3H), 7.31-7.27 (m, 2H),6.73 (d, 1H, J=8.4 Hz), 5.48-5.41 (m, 1H), 3.99-3.92 (m, 6H), 3.53-3.24(m, 8H). LC-MS: [M+H]⁺ 493.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedantiproliferative activity assays which follow have been carried outwith compounds according to the invention.

Example 92 FLT3 Kinase Assay

FLT3 kinase assay was obtained from Claiper Life Sciences (Catalog#200-0423). The assay was carried out with human recombinant FLT3 (0.287nM), fluoresce in labeled peptide substrate (with a peptide sequence ofEAIYAAPFAKKK, 1.5 μM) and test compounds (in serial dilution) using384-well plates, quantified by Caliper technology. Kinase reaction wasperformed in 100 mM HEPES, pH 7.5, 4% DMSO, 0.003% Brij-35, 0.004%tween, 10 mM MgCl₂, and 100 μM ATP (for IC₅₀ determination), incubatedat 28° C. for 90 minutes. After incubation, the reaction product wasanalyzed by electrophoretic mobility shift run on Caliper bymanufacturer's protocol.

IC₅₀ is the amount of test compound that inhibits 50% of the activity ofFLT3 in this assay. In some cases where the IC₅₀ values were notdetermined, then the % inhibition at 10 μM test compound concentrationmay be reported instead. The results of this assay for sample compoundsof the invention are provided in Table I below.

Example 93 Cell Glo Viability Assay (Luminscence)

Molm13 cells, a human acute monocytic leukemia cell line, and MV4-11cells, a human leukemia cell line known to express mutated FLT3 cells(both from ATCC) were seeded separately at 2000 cells per well in 90 μLof RPMI1640 medium supplemented with 10% FBS in 96-well black-walledplates (BD Falcon). Test compounds were diluted at ten times of assayconcentrations, 10 μL was added into duplicate wells. Plates wereincubated at 37° C. with 5% CO₂ for 5 days. Cell viability was assayedby CellTiter-Glo® Luminescent Cell Viability Assay (Promega) followingmanufacturer's protocol.

The results of this assay, given as EC₅₀ values, indicate theconcentration of test compound that inhibits tumor cell proliferation by50%. The results of this assay for sample compounds of the invention arealso provided in Table I below.

TABLE I Kinase enzyme and cellular activity Enzyme Cellular CellularIC₅₀ (μM) EC₅₀ (μM) EC₅₀ (μM) Example FLT3 Molm13 MV4-11 12 NT NT NT 13NT NT NT 14 0.045 NT NT 15 NT NT NT 16 NT NT NT 17 NT NT NT 18 NT NT NT19 NT NT NT 20 <0.005 0.052 0.041 21 0.122 NT NT 22 NT NT NT 23 1.29 NTNT 24 NT NT NT 25 NT NT NT 26 0.105 2.557 1.118 27 NT NT NT 28 NT NT NT29 0.589 NT NT 30 0.166 2.188 0.745 31 0.218 NT NT 32 0.102 NT NT 33 NTNT NT 34 NT NT NT 35 0.025 NT NT 52 0.539 NT NT 54 4.93 NT NT 55 0.54 NTNT 56 7.155 NT NT 57 1.281 NT NT 58 1.355 NT NT 59 29.2% NT NT 60 5.78NT NT 61 1.096 NT NT 63 1.83 NT NT 64 33.5% NT NT 65 1.33 NT NT 66 0.868NT NT 67 <0.005 0.049 0.017 68 <0.005 0.061 0.052 70 0.051 NT NT 7113.2% NT NT 72 0.008 0.171 0.124 73 0.006 0.077 0.04 75 0.082 1.6930.878 76 <0.005 0.301 0.232 77 <0.005 0.08 0.015 79 0.321 1.966 1.012 80<0.005 0.041 <0.014 81 0.003 0.255 0.288 82 0.01 0.119 0.049 83 <0.0050.021 0.016 84 <0.005 0.056 0.068 85 <0.005 <0.014 <0.014 86 0.064 0.3530.385 87 0.006 0.074 0.07 88 0.006 0.037 0.055 89 0.019 0.075 0.06 90<0.005 0.034 <0.014 91 <0.005 <0.014 <0.014 NT: not tested

What is claimed:
 1. A compound of formula I

wherein X is selected from CH or N, R¹ and R² are independently selectedfrom the group consisting of (a) H, (b) C₁₋₄ alkyl, (c) C₁₋₄ alkylsubstituted with up to 3 groups selected from cycloalkyl, heterocycle,OR⁵, NR⁵R⁶, SO₂R⁷ or CN, (d) heterocycle, (e) heterocycle substitutedwith up to three groups selected from C₁₋₄ alkyl, OR⁸, NR⁸R⁹ or CN, (f)cycloalkyl, and (g) cycloalkyl substituted with up to three groupsselected from C₁₋₄ alkyl, OR⁸, NR⁸R⁹ or CN; or alternatively, NR¹R²together can be a heterocycle that optionally may be substituted withC₁₋₄ alkyl; R³ is selected from the group consisting of (a) C₁₋₆ alkyl(b) C₁₋₆ alkyl substituted with up to 3 groups selected from aryl, arylsubstituted with Cl, F, CH₃, or CF₃, heteroaryl, cycloalkyl,heterocycle, OH, OCH₃, NR⁸R⁹, and CN; (c) aryl, (d) aryl substitutedwith Cl, F, C₁₋₄ alkyl or CF₃, (e) heteroaryl, (f) cycloalkyl optionallysubstituted with OR⁵, and (g) heterocycle; R⁴, R⁸ and R⁹ areindependently selected from the group consisting of (a) H, and (b) C₁₋₄alkyl; or alternatively, NR³R⁴ together can be a heterocycle thatoptionally is substituted with C₁₋₄ alkyl; R⁵ and R⁶ are independentlyselected from the group consisting of (a) H, and (b) C₁₋₄ alkyl; and R⁷is selected from the group (a) C₁₋₄ alkyl, and (b) cycloalkyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein either one of X is N, or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 wherein both X is CH, or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,wherein R¹ is C₁₋₄ alkyl, or a pharmaceutically acceptable salt thereof.5. The compound of claim 4 wherein R¹ is C₁₋₄ alkyl that optionally issubstituted with heterocycle, or a pharmaceutically acceptable saltthereof.
 6. The compound of claim 4 wherein R¹ is C₁₋₄ alkyl thatoptionally is substituted with OH, or a pharmaceutically acceptable saltthereof.
 7. The compound of claim 4 wherein R¹ is C₁₋₄ alkyl thatoptionally is substituted with SO₂R⁷ and R⁷ is C₁₋₄ alkyl, or apharmaceutically acceptable salt thereof.
 8. The compound of claim 1,wherein R¹ is cycolakyl that optionally is substituted with NR⁸R⁹, or apharmaceutically acceptable salt thereof.
 9. The compound of claim 8wherein NR⁸R⁹ is NH₂, or a pharmaceutically acceptable salt thereof. 10.The compound of claim 1, wherein R¹ is a heterocycle, or apharmaceutically acceptable salt thereof.
 11. The compound of claim 10wherein R¹ is piperazine or morpholine, or a pharmaceutically acceptablesalt thereof.
 12. The compound of claim 1, wherein R² is H, or apharmaceutically acceptable salt thereof.
 13. The compound of claim 1,wherein R² is C₁₋₄ alkyl, or a pharmaceutically acceptable salt thereof.14. The compound of claim 1, wherein NR¹R² together are a heterocyclethat optionally may be substituted with C₁₋₄ alkyl, or apharmaceutically acceptable salt thereof.
 15. The compound of claim 14wherein NR¹R² is piperazine that optionally is substituted with methyl,or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein R³ is C₁₋₆ alkyl that optionally may be substituted witharyl, heteroaryl, or herterocycle, or a pharmaceutically acceptable saltthereof.
 17. The compound of claim 16 wherein R³ is C₁₋₆ alkyl thatoptionally is substituted with up to two groups selected from thiopheneand phenyl, or a pharmaceutically acceptable salt thereof.
 18. Thecompound of claim 1, wherein R³ is cycloalkyl that optionally may besubstituted with OR⁵, or a pharmaceutically acceptable salt thereof. 19.The compound of claim 18 wherein R³ is cyclohexane that optionally maybe substituted with OH.
 20. The compound of claim 1, wherein R³ is aryl,or a pharmaceutically acceptable salt thereof.
 21. The compound of claim20 wherein R³ is phenyl, or a pharmaceutically acceptable salt thereof.22. The compound of claim 1, wherein R⁴ is H, or a pharmaceuticallyacceptable salt thereof.
 23. The compound of claim 1, wherein NR³R⁴together are a heterocycle that optionally is substituted with C₁₋₄alkyl, or a pharmaceutically acceptable salt thereof.
 24. The compoundof claim 23 wherein NR³R⁴ is morpholine or piperazine that optionallymay be substituted with methyl, or a pharmaceutically acceptable saltthereof.
 25. The compound of claim 1, wherein R⁵ and R⁶ areindependently H or CH₃, or a pharmaceutically acceptable salt thereof.26. The compound of claim 1, wherein R⁷, R⁸ and R⁹ are independentlyselected from an C₁₋₄ alkyl group, or a pharmaceutically acceptable saltthereof.
 27. A compound selected from the group comprising:Isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;2-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;(2-Methanesulfonyl-ethyl)-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;(2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-amine;4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol;Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;andPiperidin-4-yl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;or a pharmaceutically acceptable salt of any of the foregoing compounds.28. A compound selected from the group comprising:[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;4-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanol;2-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanol;2-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;2-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;2-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;and(2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;or a pharmaceutically acceptable salt of any of the foregoing compounds.29. A compound selected from the group comprising:Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;Methyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride;N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride;N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine;hydrochloride;Benzyl-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;Benzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;(2-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride;(4-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride;N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine;hydrochloride; and{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine;or a pharmaceutically acceptable salt of any of the foregoing compounds.30. A compound selected from the group comprising:1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine;hydrochloride;{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine;hydrochloride;(2-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;hydrochloride;(3-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;hydrochloride;N-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride;N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine;hydrochloride;(4-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;hydrochloride;[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;hydrochloride;N-[3-(6-Benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride;N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine;hydrochloride;N-{3-[2-(3-Amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride; andN-{3-[2-(2-Amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride; or a pharmaceutically acceptable salt of any of theforegoing compounds.
 31. A compound selected from the group comprising:1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine;hydrochloride;N-{3-[6-(2-Amino-1-phenyl-ethylamino)-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine;hydrochloride;N-{3-[6-(3-Amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride;N-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine;hydrochloride;N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine;hydrochloride;{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride;{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine;hydrochloride;1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diaminehydrochloride; and1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diaminehydrochloride; or a pharmaceutically acceptable salt of any of theforegoing compounds.
 32. A pharmaceutical composition comprising any ofthe compounds according to claim 1, or a pharmaceutically acceptablesalt thereof, as an active ingredient and a pharmaceutically acceptablecarrier or excipient.